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Background: Triple Negative Breast Cancer (TNBC) represents approximately 15% of all breast cancer. It confers a poorer prognosis relative to the other breast cancer subtypes, with an increased likelihood of recurrence and death within 5 years of diagnosis. There is no standard of care specifically for patients presenting with TNBC. Altered amino acid metabolism have been shown to play a role in TNBC. Eryaspase, asparaginase (ASNase) encapsulated in red blood cells (RBCs) is an investigational product under development. Following infusion, asparagine and glutamine are actively transported into RBCs where they are hydrolyzed by the encapsulated ASNase. In a recent randomized Phase 2b study, eryaspase has demonstrated evidence of improved overall survival (OS) and progression free survival (PFS) and acceptable safety when combined with gemcitabine or FOLFOX therapy in patients with advanced pancreatic cancer whose disease progressed following first-line treatment (NCT02195180). The demonstration of ASNase activity of eryaspase in combination with chemotherapy including DNA-damaging agents in both preclinical and clinical settings provide a rationale to further test combination in TNBC. Methods: TRYbeCA-2 is an international, randomized, open-label Phase 2/3 trial (N=64 for Phase 2) of eryaspase combined with chemotherapy in patients with locally recurrent or metastatic TNBC who have not received prior systemic therapy for locally recurrent or metastatic disease. Patients are randomized in a 1:1 ratio to receive gemcitabine/carboplatin with or without eryaspase, administered as IV infusion on Day 1 and Day 8 of each 3-week cycle. Key eligibility criteria include measurable lesion(s), performance status 0 or 1, and adequate organ function. The primary endpoint is the objective response rate (ORR) as determined by an independent radiological review. Key secondary endpoints include ORR as determined by the investigator’s assessment, clinical benefit rate, overall survival, progression-free survival, safety, biomarker research, pharmacokinetics and pharmacodynamics. A steering committee will be established to review safety at regular intervals and to review safety and efficacy data at the end of the Phase 2 to determine whether or not to proceed to Phase 3. The study is planned in European countries. Several sites have already been initiated and at least one patient was enrolled at the time of submitting this abstract. Citation Format: Ahmad Awada, Javier Cortes, Sarah Slater, Iain MacPherson, Tibor Csoszi, Jean-Baptiste Bertrand, Anne-Sophie Clermont, Rachel Pollard, Romain Chrestia-Blanchine, Nigel Biswas-Baldwin, Hagop Youssoufian, Iman El-Hariry. TRYbeCA-2: A randomized phase 2/3 study of eryaspase in combination with gemcitabine and carboplatin chemotherapy versus chemotherapy alone as first-line treatment in patients with metastatic or locally recurrent triple-negative breast cancer (NCT03674242) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-08-02.

Relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL) is an aggressive lymphoma with a median overall survival (OS) of 6 months. Most approved therapies have overall response rates (ORR) of < 30%, low complete response (CR) rates, and short progression free survival (PFS). Duvelisib (DUV), a dual PI3K-δ,γ inhibitor, is FDA approved at 25 mg twice daily (BID) for the treatment of R/R chronic lymphocytic leukemia or small lymphocytic lymphoma after ≥ 2 lines of prior therapy and R/R follicular lymphoma after ≥ 2 prior systemic therapies, the latter based on accelerated approval. DUV monotherapy demonstrated an ORR of 50% in patients (pts) with R/R PTCL in a Phase 1 study across multiple subtypes (Horwitz, Blood 2018). In the Phase 2, open-label, multi-center, PRIMO trial of DUV in R/R PTCL, the initial results of the dose-optimization phase (N=33) showed a 54% ORR in the 75 mg BID (N=13) and 35% in the 25 mg BID (N=20) cohorts by investigator assessment (INV) , the primary endpoint (Horwitz, ASH 2019). We report mature dose-optimization results and the initial results of a planned preliminary assessment (N=20) of the dose-expansion (NCT03372057; supported by Verastem Oncology). In the dose-optimization phase, pts received DUV at 25 mg (Cohort 1) or 75 mg BID (Cohort 2). Pts were evaluable if they completed 1 cycle (28 days) of DUV and had ≥ 1 efficacy assessment. The dose-expansion phase is ongoing with a targeted enrollment of 100 pts; pts were eligible if they had histologically confirmed R/R PTCL after ≥2 cycles of a prior standard regimen and a CD4 lymphocyte count of ≥ 50/mm3 (0.05 x 109/L). Based on the initial dose-optimization results, it was determined pts will receive DUV starting at 75 mg BID for 2 cycles to achieve more rapid tumor control, followed by 25 mg to try to maintain long-term disease control and mitigate the potential for later onset toxicities. Pts were to be maintained on therapy continuously until progressive disease (PD) or unacceptable toxicity. For those at 25mg BID, it was permitted for the dose to be re-escalated to 75 mg BID if an assessment shows PD and the pt had not required a dose modification due to toxicity. The primary endpoint is ORR by an Independent Review Committee (IRC), and secondary endpoints include duration of response (DOR), PFS, OS, disease control rate, and safety; all analyses consisted of pts that received at least 1 dose of DUV. The statistical analysis plan was amended to take a preliminary assessment of ORR after approximately 20 pts were evaluated for response in the dose-expansion phase, consistent with the number of pts that were evaluated in the dose-optimization phase (Cohort 2). Dose-Optimization Phase Efficacy Update: As of the data cutoff, 2 pts (1 each cohort) remain on treatment. Efficacy data are summarized in Table 1. Of those pts that achieved a CR, 1 in each cohort proceeded to undergo stem cell transplant or consolidated radiation therapy with curative intent, and are censored in the DOR assessment . Dose-Expansion Phase Initial Summary: As of the data cutoff of 23 March 2020, a total of 25 pts have been dosed, 20 of whom underwent at least 1 disease response assessment (Table 1). Pts had a median age of 61 years (range, 21-86 years) and a median of 2 prior therapies (range, 1-6). Forty-five percent (9/20) of pts remain on treatment (5 responders, 3 with assessments not yet performed, 1 on treatment with stable disease);11 pts discontinued due to PD (n=7), adverse events (n=2) , or to under go transplant (n=2). Responses occurred in 8/20 pts: PTCL-NOS (4 CR, 1 partial response [PR]), ALCL (1 PR), AITL (1 CR) and SPTCL (1 CR). The most frequent adverse events seen were neutrophil count decreased (25%), ALT increased (21%), WBC decreased (21%) and lymphocyte count decreased (21%). In summary, the DUV data observed to date show consistent response rates in a R/R PTCL pt population. The safety profile observed in PRIMO to date is consistent with the current safety profile of DUV. The mature dose-optimization phase results demonstrated a median DOR of 12.2 months for the 75 mg BID cohort. The preliminary results from the PRIMO dose-expansion cohort (75 mg BID followed by 25 mg BID dosing) show an ORR of 40 % and CR rate of 30% (6/20) by INV assessment. These data support continued evaluation of DUV as a treatment option for R/R PTCL. Updated data from the planned interim analysis after 40 pts enroll (occurred June 2020) will be presented. Disclosures Pro: Verastem Oncology: Research Funding. Brammer:Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Seattle Genetics: Honoraria, Speakers Bureau; Kymera: Honoraria; Verastem Oncology: Other: Travel. Jacobsen:Takeda: Honoraria; Merck, Pharmacyclics, F. Hoffmann-LaRoche, Novartis: Research Funding; Acerta, AstraZeneca, Merck: Consultancy. Mehta-Shah:Corvus: Research Funding; Verastem: Research Funding; Celgene: Research Funding; Bristol Myers-Squibb: Research Funding; Genetech/Roche: Research Funding; C4 Therapeutics: Consultancy; Karyopharm Therapeutics: Consultancy; Innate Pharmaceuticals: Research Funding; Kyowa Hakko Kirin: Consultancy. Zain:Seattle Genetics: Research Funding; Kyowa Kirlin: Research Funding; Mundai Pharma: Research Funding. Zinzani:Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lustgarten:Verastem Oncology: Current Employment, Current equity holder in publicly-traded company. Youssoufian:Verastem Oncology: Current Employment, Current equity holder in publicly-traded company. Horwitz:Janssen: Consultancy; GlaxoSmithKline: Consultancy; Daiichi Sankyo: Research Funding; C4 Therapeutics: Consultancy; Beigene: Consultancy; Portola: Consultancy, Research Funding; Mundipharma: Consultancy; Innate Pharma: Consultancy; Corvus: Consultancy; Trillium: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Infinity/Verastem: Research Funding; Forty Seven: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Aileron: Consultancy, Research Funding; ADCT Therapeutics: Consultancy, Research Funding; Vividion Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Myeloid Therapeutics: Consultancy; Miragen: Consultancy; Kura Oncology: Consultancy; ASTEX: Consultancy; Affirmed: Consultancy. OffLabel Disclosure: Duvelisib (DUV), a dual PI3K-δ,γ inhibitor, is FDA approved at 25 mg twice daily (BID) for the treatment of R/R chronic lymphocytic leukemia or small lymphocytic lymphoma after at least 2 lines of prior therapy and R/R follicular lymphoma after at least 2 prior systemic therapies, the latter based on accelerated approval. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Duvelisib is not approved for Peripheral T-Cell Lymphoma. This study is investigating treatment or outcomes that have not received approval from a Health Authority. The information presented is not intended to convey conclusions of safety or efficacy. There is no guarantee that the outcome of these studies will result in approval by a Health Authority.

Purpose: In the phase III DUO trial, duvelisib, an oral dual PI3K-δ,γ inhibitor, demonstrated significantly improved efficacy versus ofatumumab [median (m) progression-free survival (PFS), 13.3 vs. 9.9 months (HR, 0.52; P < 0.0001); overall response rate [ORR], 74% vs. 45% (P < 0.0001)], with a manageable safety profile in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). We report results from patients with progressive disease (PD) after ofatumumab who crossed over to duvelisib in the DUO trial. Patients and Methods: Patients with radiographically confirmed PD after ofatumumab received duvelisib 25 mg twice daily in 28-day cycles until PD, intolerance, death, or study withdrawal. The primary endpoint was ORR per investigator. Secondary endpoints included duration of response (DOR), PFS, and safety. Results: As of December 14, 2018, 90 ofatumumab-treated patients in the DUO trial prior to crossover had an ORR of 29%, mDOR of 10.4 months, and mPFS of 9.4 months. After crossover, 77% of patients (69/90) achieved a response, with an mDOR of 14.9 months and mPFS of 15.7 months. Patients with del(17p) and/or TP53 mutations had similar outcomes [ORR, 77% (20/26); mPFS, 14.7 months]. Notably, 73% of patients (47/64) with disease previously refractory to ofatumumab achieved a response. The most frequent any-grade/grade 3/4 treatment-emergent adverse events were diarrhea (47%/23%), neutropenia (26%/23%), pyrexia (24%/4%), cutaneous reactions (23%/4%), and thrombocytopenia (10%/6%). Conclusions: Duvelisib demonstrated high response rates with good durability and a manageable safety profile in patients with R/R CLL/SLL who progressed on ofatumumab, including patients with high-risk disease and disease previously refractory to ofatumumab.

TPS453 Background: FOLFIRINOX remains the standard of care for the first line treatment of patients with locally advanced and metastatic pancreatic adenocarcinoma, however the prognosis remains poor, thus novel treatment options are indicated. Eryaspase, asparaginase (ASNase) encapsulated in red blood cells (RBCs) is an investigational product under development. Following infusion, asparagine and glutamine are actively transported into RBCs where they are hydrolyzed by the encapsulated ASNase. A randomized phase IIb study in patients with advanced pancreatic cancer whose disease progressed following first-line treatment (NCT02195180) was previously conducted. Eryaspase in combination with gemcitabine monotherapy or FOLFOX combination therapy improved overall survival (OS) and progression free survival (PFS). The safety profile of eryaspase was acceptable. A second line pivotal randomized phase III trial (Trybeca-1) is currently enrolling (NCT03665441). We design this phase I study to determine the safety of mFOLFIRINOX combined with Eryaspase in the first line of treatment. Methods: Patients with locally or metastatic biopsy proven pancreatic adenocarcinoma will be treated with the combination of mFOLFIRINOX plus Eryaspase. This will be a standard 3+3 design with 4 possible doing levels. mFOLFIRINOX dosing will include 5-Fluorouracil 2400 mg/m2 over 46 hours, Oxaliplatin 85 mg/m2, Irinotecan 150 mg/m2 plus Eryaspase 75 Units/kg at dose level 0. Eryaspase will be dose escalated up to 100 Units/kg. The study will enroll at three academic centers. Key eligibility criteria include performance status 0 or 1; locally advanced or metastatic tumor disease; adequate organ function. The primary objective is to determine the maximum tolerated dose and safety of this novel combination. Key secondary objectives include objective response rate, progression-free survival, overall survival, pharmacokinetics, pharmacodynamics, and biomarker research. A data safety monitoring committee will review data every 3 months. Clinical trial information: 04292743.

Advancing nanomedicines from concept to clinic requires integration of new science with traditional pharmaceutical development. The medical and commercial success of nanomedicines is greatly facilitated when those charged with developing nanomedicines are cognizant of the unique opportunities and technical challenges that these products present. These individuals must also be knowledgeable about the processes of clinical and product development, including regulatory considerations, to maximize the odds for successful product registration. This article outlines these topics with a goal to accelerate the combination of academic innovation with collaborative industrial scientists who understand pharmaceutical development and regulatory approval requirements-only together can they realize the full potential of nanomedicines for patients.

TPS4666 Background: Second-line treatment options for advanced pancreatic adenocarcinoma are currently limited. Eryaspase, asparaginase (ASNase) encapsulated in red blood cells (RBCs) is an investigational product under development. Following infusion, asparagine and glutamine are actively transported into RBCs where they are hydrolyzed by the encapsulated ASNase. We have recently reported the outcome of a randomized Phase 2b study inpatients with advanced pancreatic cancer whose disease progressed following first-line treatment(NCT02195180). Eryaspase in combination with gemcitabine monotherapy or FOLFOX combination therapy improved overall survival (OS) and progression free survival (PFS). The safety profile of eryaspase was acceptable. The results of this Phase 2b study provided a rationale for initiating this confirmatory Phase 3 pivotal trial (TRYbeCA-1). Methods: TRYbeCA-1 is a randomized, open-label Phase 3 trial (N = ~500) of eryaspase combined with chemotherapy in patients with adenocarcinoma of the pancreas who have failed only one prior line of systemic anti-cancer therapy for advanced pancreatic cancer and have measurable disease. Patients are randomized in a 1:1 ratio to receive gemcitabine/Abraxane or irinotecan-based therapy (FOLFIRI [FOLinic acid-Fluorouracil-IRInotecan regimen] or irinotecan liposome injection/5-fluorouracil/leucovorin) with or without eryaspase, administered as IV infusion on Day 1 and Day 15 of each 4-week cycle. Key eligibility criteria include performance status 0 or 1; stage III-IV disease; documented evidence of disease progression; available tumor tissue; and adequate organ function. The primary endpoint is OS. Key secondary endpoints include PFS and objective response rate, safety, quality of life, pharmacokinetics and pharmacodynamics, and biomarker research. A hazard ratio in OS of 0.725 is being targeted which represents a conservative estimate based on the Phase 2b data and is viewed as being highly clinically relevant. An IDMC is established to review safety at regular intervals andto review efficacy data at the planned interim and final analyses. IDMC last reviewed the trial in October 2019 and suggested the trial continue as planned. Clinical trial information: NCT03665441 .

Prostate cancer is the leading cause of cancer-related death in men in the United States. A major cause of drug resistance in prostate and other epithelial tumors may be due to the presence of a fraction of tumor cells that retain the ability to initiate tumors and hence are termed tumor-initiating cells (TIC) or cancer stem cells. Here, we report that darinaparsin, an organic derivative of arsenic trioxide, is cytotoxic to prostate cancer cell lines as well as fresh prostate cancer cells from patients at low micromolar concentrations, and importantly inhibits the TIC subpopulations. It also inhibits growth of the castrate-resistant Du145 prostate tumor propagated as xenograft in mice and inhibits the tumor-initiating potential of prostate cancer cells. Although the mechanism by which darinaparsin acts is not completely known, we show that it kills prostate cancer cells by blocking cells in the G2–M phase of the cell cycle and inhibits Hedgehog signaling by downregulating Gli-2 transcriptional activity. These data provide a rationale for evaluating darinaparsin in patients with castrate-resistant prostate cancer. Mol Cancer Ther; 14(1); 23–30. ©2014 AACR.

Background: Second-line treatment options for advanced pancreatic adenocarcinoma are currently limited. Eryaspase, asparaginase (ASNase) encapsulated in red blood cells (RBCs), is an investigational product under development. Following infusion, asparagine and glutamine are actively transported into RBCs where they are hydrolyzed by the encapsulated ASNase. We have recently reported the outcome of a randomized phase 2b study in patients with advanced pancreatic cancer whose disease progressed following first-line treatment (NCT02195180). Eryaspase in combination with gemcitabine monotherapy or FOLFOX combination therapy improved overall survival (OS) and progression-free survival (PFS). The safety profile of eryaspase was acceptable. The results of this phase 2b study provided a rationale for initiating this confirmatory phase 3 pivotal trial (TRYbeCA-1). Methods: TRYbeCA-1 is an international, randomized, open-label phase 3 trial (N= ~500) of eryaspase combined with chemotherapy in patients with adenocarcinoma of the pancreas who have failed only one prior line of systemic anticancer therapy for advanced pancreatic cancer and have measurable disease. Patients are randomized in a 1:1 ratio to receive gemcitabine/abraxane or irinotecan-based therapy (FOLFIRI [FOLinic acid-Fluorouracil-IRInotecan regimen] or irinotecan liposome injection/5-fluorouracil/leucovorin) with or without eryaspase, administered as IV infusion on Day 1 and Day 15 of each 4-week cycle. Key eligibility criteria include performance status 0 or 1, stage IV disease, documented evidence of disease progression, available tumor tissue, and adequate organ function. The primary endpoint is OS. Key secondary endpoints include PFS and objective response rate, safety, quality of life, pharmacokinetics and pharmacodynamics, and biomarker research. A hazard ratio in OS of 0.725 is being targeted, which represents a conservative estimate based on the phase 2b data and is viewed as being highly clinically relevant. An IDMC will be established to review safety at regular intervals and to review efficacy data at the planned interim and final analyses. Citation Format: Pascal Hammel, Rosanna Berardi, Eric Van Cutsem, Jaime Feliu, Richard Greil, Harpreet Wasan, Jean-Philippe Metges, Peter Nygren, Pia Österlund, Marcus Noel, Thomas Seufferlein, Geert-Jan Creemers, Anu Gupta, Sophie Salesse, Nigel Biswas-Baldwin, Hedy Dion, Hagop Youssoufian, Iman El-Hariry, Manuel Hidalgo. Trybeca-1: A randomized, phase 3 study of eryaspase in combination with chemotherapy versus chemotherapy alone as second-line treatment in patients with pancreatic adenocarcinoma (NCT03665441) [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B22.

Introduction Relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL) carries a poor prognosis, with most approved therapies having response rates of < 30% and limited progression-free survival (PFS). Duvelisib (DUV), a dual PI3K-δ,γ inhibitor, is FDA approved at 25 mg twice daily (BID) for the treatment of R/R chronic lymphocytic leukemia or small lymphocytic lymphoma after ≥ 2 lines of prior therapy and R/R follicular lymphoma after ≥ 2 prior systemic therapies. DUV exhibited potent activity against T-cell lymphoma cell lines in vitro, and DUV monotherapy at 25 or 75 mg BID demonstrated clinical activity in patients (pts) with R/R peripheral T-cell lymphoma (PTCL) in phase 1 studies [overall response rate (ORR), 50%] across multiple subtypes (Horwitz et al. Blood 2018; Horwitz et al. 2019 ICML). The phase 2 PRIMO trial was designed to determine an optimal regimen of DUV monotherapy in R/R PTCL and characterize the efficacy and tolerability of DUV in this disease. We report the results for the dose-optimization phase of the PRIMO trial (NCT03372057). Methods In the dose-optimization phase, pts with R/R PTCL, ECOG performance score of ≤ 2, and no history of allogeneic stem cell transplant were randomized to receive DUV 25 mg BID with an option for dose escalation (cohort 1) or DUV 75 mg BID (cohort 2) continuously until development of progressive disease or unacceptable toxicity (cycle = 28 days). The primary endpoint was investigator-assessed ORR, and secondary endpoints included duration of response and safety. Results A total of 33 pts (cohort 1, n = 20; cohort 2, n = 13) were treated in the dose-optimization phase (Table). Pts had a median of 1.5 years (range, 0.3-12.7 years) from initial diagnosis and a median of 2 prior therapies (range, 1-8). Patients were evaluable if they completed 1 cycle of DUV and had ≥ 1 efficacy assessment. Nonevaluable patients could be replaced. Response was assessed in the evaluable and overall populations. All patients in cohort 2 and 13 of 20 patients in cohort 1 were able to complete 1 cycle of therapy. Seven patients in cohort 1 discontinued therapy early due to disease progression and/or toxicity. Low CD4 counts (< 50 cells/mm3; Common Terminology Criteria for Adverse Events grade 4) were associated with early discontinuation of DUV. Most responses (cohort 1, 5/7; cohort 2, 6/7) were observed at the end of cycle 1. At a median follow-up of 20 weeks, the majority of responders (cohort 1, 4/7; cohort 2, 6/7) were still in response at the time of their last assessment. ORR as assessed by blinded independent central review could be determined for 31 patients and was 42% in cohort 1 and 67% in cohort 2. Table. Analysis Populations and Investigator-Assessed Response Pharmacokinetic analysis demonstrated a dose-related increase in exposure, with ≈ 2-fold increase in the steady-state exposure of DUV at the 75 vs 25 mg BID dosage, suggesting that adequate exposure can be more rapidly and reliably achieved with a higher dose of DUV. No differences were observed in pharmacodynamic markers (pAKT in monocytes and B cells) at 25 and 75 mg dose levels. The most common (≥ 3 patients) grade ≥ 3 adverse events (AEs) in all patients receiving DUV were neutropenia (7), thrombocytopenia (5), and sepsis (4), with disease progression, pneumonia, aspartate aminotransferase elevation, lymphopenia, dyspnea, and rash observed in 3 patients. Serious AEs occurring in ≥ 2 patients were colitis, pyrexia, disease progression, sepsis, pneumonia, hyponatremia, dyspnea, pneumonitis, and respiratory failure. Overall, 12% of pts receiving DUV discontinued due to an AE. Conclusions These findings confirm that both 25 and 75 mg BID starting dosages of DUV are clinically active in pts with R/R PTCL, with complete responses in both cohorts. There were no unexpected toxicities. Early progression was seen more frequently in the 25 mg cohort, and higher initial exposure may be important in aggressive diseases. The expansion phase of the PRIMO trial will investigate DUV starting at 75 mg BID for 2 cycles to achieve rapid tumor response, followed by 25 mg BID to maintain long-term disease control and mitigate the potential for later onset toxicity. Disclosures Horwitz: Miragen: Consultancy; Celgene: Consultancy, Research Funding; Aileron: Research Funding; Aileron: Research Funding; Seattle Genetics: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin: Consultancy; Astex: Consultancy; Affimed: Consultancy; Kura: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Portola: Consultancy; Affimed: Consultancy; Celgene: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Innate Pharma: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Astex: Consultancy; ADCT Therapeutics: Research Funding; Portola: Consultancy; Mundipharma: Consultancy; Aileron: Research Funding; Portola: Consultancy; Forty-Seven: Research Funding; Trillium: Research Funding; Aileron: Research Funding; Celgene: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Kura: Consultancy; Seattle Genetics: Consultancy, Research Funding; Astex: Consultancy; Forty-Seven: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADCT Therapeutics: Research Funding; Astex: Consultancy; Miragen: Consultancy; Kyowa Hakko Kirin: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Affimed: Consultancy; Miragen: Consultancy; Mundipharma: Consultancy; Innate Pharma: Consultancy; Forty-Seven: Research Funding; Celgene: Consultancy, Research Funding; Innate Pharma: Consultancy; Innate Pharma: Consultancy; Mundipharma: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Research Funding; Affimed: Consultancy; Kyowa Hakko Kirin: Consultancy; Trillium: Research Funding; Forty-Seven: Research Funding; Kyowa Hakko Kirin: Consultancy; Kura: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Miragen: Consultancy; Trillium: Research Funding; Kura: Consultancy; Mundipharma: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Trillium: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Portola: Consultancy; ADCT Therapeutics: Research Funding. Mehta-Shah:Kiowa Hakka Kirin: Consultancy; Roche/Genentech: Research Funding; Bristol Myers Squibb: Research Funding; Verastem Pharmaceuticals: Research Funding; Celgene: Research Funding; Innate Pharmaceuticals: Research Funding. Pro:Takeda: Consultancy, Honoraria, Other: Travel Expenses; Celgene: Consultancy, Honoraria; Kyowa Hakka Kirin: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Other: Travel Expenses, Research Funding. Jacobsen:Pharmacyclics: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Takeda: Honoraria; Acerta: Consultancy; Astra-Zeneca: Consultancy; F. Hoffmann-LaRoche: Research Funding. Casulo:Celgene: Research Funding; Gilead: Honoraria, Other: Travel, accommodation, expenses; Roche: Other: Travel, accommodation, expenses. Brammer:Celgene: Research Funding; Seatlle Genetics: Honoraria, Speakers Bureau. Haney:Verastem Inc: Employment, Equity Ownership. Youssoufian:Verastem Oncology: Consultancy, Equity Ownership. Weaver:Verastem Oncology: Employment, Equity Ownership, Patents & Royalties: Inventor; Hillstream Biopharma: Consultancy, Equity Ownership; FemtoDx: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Inventor. Baglio:Verastem Oncology: Employment. Narasimhan:Verastem: Employment, Equity Ownership. Zain:Spectrum: Consultancy; Seattle Genetics: Consultancy. OffLabel Disclosure: Duvelisib (DUV), a dual PI3K-delta,gamma inhibitor, is US FDA approved at 25 mg twice daily (BID) for the treatment of R/R chronic lymphocytic leukemia or small lymphocytic lymphoma after at least 2 lines of prior therapy and R/R follicular lymphoma after at least two prior systemic therapies.

Background: Myelofibrosis (MF) is a life-threatening disease characterized by splenomegaly, constitutional symptoms, and shortened survival. Although ruxolitinib, a JAK1/2 inhibitor, is approved for Intermediate or High-risk MF and can reduce the spleen size and improve quality of life, many patients discontinue due to loss of efficacy. In preclinical models, the activity of mutated JAK2 is tightly regulated by epichaperomes, a complex network of proteins which forms under cellular stress, such as cancer, and nucleates on heat shock protein 90 (Hsp90), which in turn assumes a specific conformation in its ATP binding domain. PU-H71 is a first-in-class inhibitor of tumor epichaperome-specific Hsp90, which potently kills cancer cells via disruption of the epichaperome and degradation of JAK2 as well as other client proteins. Prior dose-ranging studies of PU-H71 administered intravenously to patients with cancer identified a safe and tolerable dose. In this study, we assess an oral formulation of PU-H71 and evaluate the hypothesis that its cancer-specific mechanism combined with ruxolitinib may result in added clinical benefit as well as a wider therapeutic window. Methods: This is a multicenter, Phase 1b study with dose escalation and expansion cohorts designed to assess the safety, tolerability, PK, and preliminary efficacy of PU-H71 in patients with PMF, Post-PV MF, Post ET MF. Up to 24 patients who have active disease and receiving ≥3 months of ruxolitinib therapy (and on a stable dose for 8 weeks before starting therapy with PU-H71) will be enrolled. Evidence of persistent or worsening disease consisting of disease-related symptoms and splenomegaly of at least 5 cm below the costal margin as measured by physical examination are required. Additional inclusion criteria include a baseline platelet count of ≥50,000/mL and AST/ALT ≤2 x Upper Limit of Normal. Patients with a QT interval corrected using Fridericia's formula (QTcF) >480 ms (corrected) or left ventricular ejection fraction (LVEF) ≤50% are excluded. The study will employ a standard 3+3 dose escalation design beginning with 50 mg/day to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D), with additional patients treated in a dose expansion cohort. Response to treatment will be assessed by the 2013 revised International Working Group-Myeloproliferative Neoplasm Research and Treatment and European Leukemia Net. Additional assessments will include symptom burden assessment using the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score, bone marrow histology, JAK2V617F allele burden, serum cytokine profiles, flow cytometry of peripheral blood mononuclear cells for epichaperome status, and pharmacokinetic studies. Enrollment is ongoing. Clinical trial information: NCT03935555. Disclosures Pemmaraju: abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding; mustangbio: Consultancy, Research Funding. Gundabolu:Samus Therapeutics: Research Funding; Novartis: Consultancy; Pfizer: Consultancy; Jazz pharmaceuticals: Consultancy. Pettit:Samus Therapeutics: Research Funding. Talpaz:Imago BioSciences: Consultancy, Research Funding; Incyte: Research Funding; Constellation: Research Funding; CTI BioPharma: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Research Funding; Samus Therapeutics: Research Funding. Podoltsev:Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Kartos Therapeutics: Research Funding; Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Research Funding; Astellas Pharma: Research Funding; Daiichi Sankyo: Research Funding; Sunesis Pharmaceuticals: Research Funding; AI Therapeutics: Research Funding; Jazz Pharmaceuticals: Research Funding; Pfizer: Research Funding; Astex Pharmaceuticals: Research Funding; CTI Biopharma: Research Funding; Celgene: Other: Grant funding, Research Funding; Samus Therapeutics: Research Funding; Arog Pharmaceuticals: Research Funding; Agios Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Schiller:Amgen: Other, Research Funding; Biomed Valley Discoveries: Research Funding; Astellas: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Genzyme: Research Funding; Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Onconova: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Sangamo Therapeutics: Research Funding; Bristol Myer Squibb: Research Funding; Celgene: Research Funding, Speakers Bureau; Constellation Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Agios: Research Funding, Speakers Bureau. Eisenberg:Samus Therapeutics: Research Funding. Youssoufian:Samus Therapeutics: Consultancy. Duggan:Samus Therapeutics: Employment. Wallner:Samus Therapeutics: Employment. Verstovsek:Celgene: Consultancy, Research Funding; NS Pharma: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy; Gilead: Research Funding; Protaganist Therapeutics: Research Funding; Novartis: Consultancy, Research Funding; Roche: Research Funding; Incyte: Research Funding; Genetech: Research Funding; CTI BioPharma Corp: Research Funding; Blueprint Medicines Corp: Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Promedior: Research Funding.

Background Duvelisib, an oral dual PI3K-δ and PI3K-γ inhibitor, is approved by the US Food and Drug Administration for the treatment of adult patients with relapsed or refractory (R/R) follicular lymphoma (FL) after ≥ 2 prior systemic therapies. In multiple phase 1-3 studies that included patients with iNHL, duvelisib was shown to be efficacious, with a favorable risk-benefit profile. This study will evaluate whether duvelisib efficacy at the approved 25 mg twice daily (BID) dose can be achieved and maintained with an acceptable or improved safety profile by the inclusion of prespecified 2-week drug holidays in patients with R/R iNHL. Study Design and Methods TEMPO is a randomized, open-label, multicenter, international, phase 2 study of duvelisib in adult patients with R/R iNHL in whom ≥ 1 line of prior therapy has failed. The primary objective is to evaluate the efficacy of duvelisib administered with prescribed drug holidays, with the primary endpoint of overall response rate (ORR) by the 2007 revised International Working Group criteria. Key secondary endpoints include ORR by the 2014 Lugano criteria, progression-free survival, overall survival, time to treatment failure, duration of response, lymph node response rate, time to the first response, adverse event profile, and determination of pharmacokinetics parameters. Exploratory objectives include assessment of quality of life and biomarkers of treatment response and toxicity. Key inclusion criteria include histologically confirmed FL grades 1 to 3a, marginal zone lymphoma (splenic, nodal, or extranodal) or small lymphocytic lymphoma, radiological evidence of disease progression and ≥ 1 bidimensionally measurable lesion ≥ 1.5 cm, adequate organ function, and Eastern Cooperative Oncology Group performance status ≤ 2. Key exclusion criteria include prior allogeneic hematopoietic stem cell transplant; previous treatment with a PI3K inhibitor; history of drug-induced colitis or drug-induced pneumonitis; ongoing treatment for systemic infection; central nervous system NHL; prolonged QT interval; history of tuberculosis treatment within the 2 past years; history of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia requiring medication or mechanical control within the past 6 months; history of or concurrent interstitial lung disease of any severity and/or severely impaired lung function; ongoing treatment with chronic immunosuppressants; and any unstable or severe uncontrolled medical condition. A total of 102 patients are planned to be enrolled. Patients will be randomized 1:1 to 2 arms and stratified by number of prior therapies (1 or > 1), bulky disease status (longest diameter of baseline lesion < 5 cm or ≥ 5 cm), and time since last recurrence (≥ 24 months or < 24 months). In arm 1, patients will receive duvelisib 25 mg BID for one 10-week (W) cycle followed by 25 mg BID on W3 and W4 of each subsequent 4-week cycle. In arm 2, patients will receive duvelisib 25 mg BID on W1, W2, W5, W6, W9, and W10 of one 10-week cycle and then on W3 and W4 of each subsequent 4-week cycle. Patients will be treated until disease progression, unacceptable toxicity, or withdrawal. This study will test the null hypothesis that the ORR in each arm is ≤ 30% against the alternative that the ORR is ≥ 55%. The study has a 2-stage design. In stage 1, 15 patients will be enrolled in each arm, with response assessment after ≥ 3 cycles. If there are fewer than 6 partial or complete responses, consideration may be given to terminating the arm. Otherwise, in stage 2, 36 additional patients will be enrolled, for a total of 51 per arm. Enrollment is planned to be initiated in August 2019. Approximately 50 sites will be open for enrollment across the United States, Europe, and Asia. Disclosures Karmali: Takeda, BMS: Other: Research Funding to Institution; Gilead/Kite; Juno/Celgene: Consultancy, Speakers Bureau; Astrazeneca: Speakers Bureau. Youssoufian:Verastem Oncology: Consultancy, Equity Ownership. Sprott:SMOC Therapeutics: Employment, Equity Ownership; Verastem Oncology: Employment, Equity Ownership. Weaver:FemtoDx: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Inventor; Verastem Oncology: Employment, Equity Ownership, Patents & Royalties: Inventor; Hillstream Biopharma: Consultancy, Equity Ownership. Narasimhan:Verastem: Employment, Equity Ownership. Lustgarten:Verastem: Employment. Patrick:Verastem Oncology: Employment. Zalutskaya:Verastem Inc: Employment, Equity Ownership. Gordon:Gilead: Other: Advisory Board; Juno/Celgene: Other: Advisory Board, Research Funding; Zylem LLC: Other: co-founder; research in nanoparticles in cancer; Bayer: Other: Advisory Board. OffLabel Disclosure: Duvelisib (DUV), a dual PI3K-delta,gamma inhibitor, is US FDA approved at 25 mg twice daily (BID) for the treatment of R/R chronic lymphocytic leukemia or small lymphocytic lymphoma after at least 2 lines of prior therapy and R/R follicular lymphoma after at least two prior systemic therapies.

Background Triple Negative Breast Cancer (TNBC) represents approximately 15% of all breast cancer. It confers a poorer prognosis relative to the other breast cancer subtypes, with an increased likelihood of recurrence and death within 5 years of diagnosis. There is no standard of care specifically for patients presenting with TNBC. Altered amino acid metabolism have been shown to play a role in TNBC. Eryaspase, asparaginase (ASNase) encapsulated in red blood cells (RBCs) is an investigational product under development. Following infusion, asparagine and glutamine are actively transported into RBCs where they are hydrolyzed by the encapsulated ASNase. In a recent randomized phase 2b study, eryaspase has demonstrated evidence of improved overall survival (OS) and progression free survival (PFS) and acceptable safety when combinedwith gemcitabine or FOLFOX therapyinpatients with advanced pancreatic cancer whose disease progressed following first-line treatment (NCT02195180). The demonstration of ASNase activity of eryaspase in combination with chemotherapy including DNA-damaging agents in both preclinical and clinical settings provide a rationale to further test combination in TNBC. Trial design TRYbeCA-2 is an international, randomized, open-label phase 2/3 trial (N = 64 for phase 2) of eryaspase combined with chemotherapy in patients with locally recurrent or metastatic TNBC who have not received prior systemic therapy for locally recurrent or metastatic disease. Patients are randomized in a 1:1 ratio to receive gemcitabine/carboplatin with or without eryaspase, administered as IV infusion on Day 1 and Day 8 of each 3-week cycle. Key eligibility criteria include measurable lesion(s), performance status 0 or 1, and adequate organ function. The primary endpoint is the objective response rate (ORR) as determined by an independent radiological review. Key secondary endpoints include ORR as determined by the investigator’s assessment, clinical benefit rate, overall survival, progression-free survival, safety, biomarker research, pharmacokinetics and pharmacodynamics. Clinical trial identification NCT03674242. Legal entity responsible for the study Erytech. Funding Erytech. Disclosure J. Bertrand: Shareholder / Stockholder / Stock options, Full / Part-time employment: Erytech. A. Clermont: Shareholder / Stockholder / Stock options, Full / Part-time employment: Erytech. R. Pollard: Shareholder / Stockholder / Stock options, Full / Part-time employment: Erytech. R. Chrestia-Blanchine: Shareholder / Stockholder / Stock options, Full / Part-time employment: Erytech. N. Biswas-Baldwin: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Erytech. I. El-Hariry: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Erytech. All other authors have declared no conflicts of interest.

7523 Background: Duvelisib (DUV), a first-in-class oral dual PI3K-δ,γ inhibitor, is approved for treatment (tx) of R/R CLL/SLL after ≥ 2 prior therapies. In the phase 3 DUO trial, DUV 25 mg BID significantly improved efficacy vs ofatumumab (OFA; mPFS, 13.3 vs 9.9 mo; HR, 0.52 [ P < .0001]; ORR, 74% vs 45% [ P < .0001]) in pts with R/R CLL/SLL. Tx-emergent AEs (TEAEs) of special interest (AESIs) such as infections, diarrhea, colitis, neutropenia, rash, ALT/AST elevation, and pneumonitis, were moderate and manageable with early intervention and dose modification. We examined dose-modification patterns and their impact on response to DUV in the DUO trial. Methods: Dose interruptions (DI) or reductions (DR) to 15, 10, or 5 mg BID were permitted per study protocol to manage TEAEs. Responses were assessed by IRC. Results: Among 158 DUV-treated pts, median duration of DUV exposure was 11.6 mo (vs 5.3 mo, OFA). DI and DR occurred in 80% (126/158) and 27% (43/158) of pts, respectively. The most common cause of DI was diarrhea (23%), followed by neutropenia (12%) and pneumonia or colitis (11% each). Among responders (n = 118), median time to first response on DUV was 1.9 mo and estimated median duration of response was 11.1 mo. Median time to first DI was 3.9 mo and median duration of DI was 15 d (range, 1-133 d). Response to DUV was improved or maintained in most pts evaluated for response who had ≥ 1 DI for > 1 wk (84% [42/50]) or > 2 wk (82% [31/38]) followed by ≥ 3 wk on DUV. In a landmark analysis, median PFS was similar in pts with DI and those without DI for > 1 wk (17.8 vs 16.3 mo) or > 2 wk (17.8 vs 16.3 mo) within the first 3 mo. The median time to DR after CR/PR was 5.6 mo (n = 25) and median duration was 3.4 mo. Median time to onset across AESIs after starting DUV ranged from 2.2 to 4.3 mo; median time to resolution was within 4 wk across AESIs. Proportions of pts experiencing AESIs were stable or decreased over time after 3-6 mo: 0-3 mo, 64% (101/158); > 3-6 mo, 63% (86/137); > 6-9 mo, 47% (54/114); > 9-12 mo, 52% (52/100), and seldom led to discontinuation of DUV (≤ 10%). Conclusions: DI/DR can contribute to the effective management of TEAEs with DUV. These findings suggest that DI of > 1-2 weeks or more do not appear to significantly impact response to DUV or PFS. Clinical trial information: NCT02004522.

Despite significant advances in understanding of molecular pathobiology, the adoption of this knowledge and its application to drug development is sporadic. Consequently, the drug development process has remained intrinsically laborious and inefficient. Translational research seeks to improve this process by integrating scientific advances into well-defined clinical challenges and opportunities. The focus of this article is on cancer therapeutics, specifically, 2 biotechnology organizations' advances in oncology: (1) optimizing the safety and efficacy of a novel DNA cross-linking small molecule, palifosfamide, and (2) bringing synthetic biology into clinical practice using a controllable gene therapy strategy with intratumorally injected interleukin-12 DNA, a potent cytokine.

Introduction We conducted a phase II study of dual-agent monoclonal antibody therapy consisting of cetuximab and bevacizumab in combination with paclitaxel and carboplatin chemotherapy in non–small-cell lung cancer. Methods Patients with stage IIIB/IV nonsquamous non–small-cell lung cancer randomly received cetuximab (400 mg/m 2 initially, 250 mg/m 2 weekly thereafter) plus bevacizumab (15 mg/kg) for six cycles combined with paclitaxel (200 mg/m 2 ) and carboplatin (area under the curve 6) for either six cycles (six-cycle arm) or the first three cycles (three-cycle arm) (one cycle=3 weeks). The primary objective was progression-free survival (PFS), estimated separately for each treatment arm. Results In 121 patients, the median PFS was 6.05 months (95% confidence interval [CI]: 5.65, 7.03) in the six-cycle arm and 4.50 months (95% CI: 4.01, 5.42) in the three-cycle arm. Respective median overall survival times were 12.06 months (95% CI: 9.40, 19.25) and 11.63 months (95% CI: 6.64, 17.61). The tumor response rate was 51.7% (95% CI: 39.0%, 64.3%) and 44.3% (95% CI: 31.8%, 56.7%) in the six-cycle and three-cycle arms, respectively, with corresponding median response durations of 4.86 months (95% CI: 4.30, 7.16) and 3.94 months (95% CI: 2.92, 4.47). Quality of life was consistent across arms. Cetuximab-related grade 3/4 events in greater than 5% of patients (six-cycle arm, three-cycle arm) were dermatitis acneiform (6.9%; 8.6%) and fatigue (13.8%; 5.2%). Three patients died during the study from drug-related adverse events (one in the six-cycle arm and two in the three-cycle arm). Conclusions Both the regimens showed expected PFS and numerically comparable overall survival. Quality of life was similar in the two arms, and both the regimens were well tolerated.

O1 IL-15 primes an mTOR-regulated gene-expression program to prolong anti-tumor capacity of human natural killer cells #### Andreas Lundqvist1, Vincent van Hoef1, Xiaonan Zhang1, Erik Wennerberg2, Julie Lorent1, Kristina Witt1, Laia Masvidal Sanz1, Shuo Liang1, Shannon Murray3, Ola Larsson1

Background: Indibulin (ZI0-301) is a novel, oral, synthetic small molecule microtubule inhibitor which binds tubulin at a different site than taxanes and vinca alkaloids. Preclinical data demonstrate indibulin does not interact with acetylated (neuronal) tubulins and in clinical studies has not exhibited the neurotoxicity associated with other tubulin binders. Indibulin has potent antitumor activity in human cancer cell lines, including multidrug-, taxane-, and vinblastine-resistant. Norton-Simon modeling based on cell line data suggested that dose dense (dd) administration could optimize efficacy while limiting toxicity. Methods: Eligible patients (pts) have metastatic or unresectable locally advanced breast cancer, ECOG performance status ≤ 2, adequate organ function, measurable or nonmeasurable disease and any number of prior therapies. Uncontrolled gastrointestinal malabsorption syndrome and grade 2 or higher peripheral neuropathy are the principal exclusions. Adverse events (AEs) are graded by CTCAE v. 4.0. Objective disease status is evaluated according to RECIST 1.1. The primary objective of the phase (Ph) I portion of the study is to determine the maximum tolerated dose (MTD) of indibulin when given in dd fashion 5 days treatment, 9 days rest using standard 3+3 dose escalation schema. The secondary objectives are to evaluate safety profile at various dosing levels, pharmacokinetics (PK) and preliminary activity of indibulin. Once the MTD is defined, a food effect cross- over group (N = 12) will be enrolled. Two groups of 6 pts each will be treated in either the fed or fasted state during the first cycle. A subgroup of 13 pts consisting of 12 pts from the food effect group plus the last pt from the MTD cohort will be evaluated for PFS at 4 months and will serve as the population for the first stage of a Simon two-stage design. If 4 or more out of 13 pts do not progress at 4 months, the Ph II portion of the study will be opened. Results: Twenty one pts (20 F, 1 M) have been enrolled to cohorts 1 through 6 and the dose escalation is ongoing. Preliminary safety and efficacy data have been analyzed for 18 pts treated in cohorts 1 through 5 and are presented henceforth. No DLT has been observed and no MTD has been reached. Median age 58 years (32–81). PS 0=4, 1=12, 2=2. Median number of prior therapies 5 (1–12). Most frequent treatment-emergent AEs were: anorexia, constipation, cough, nausea (each in 39% pts); dyspnea (33%); fatigue, vomiting (each 28%). There were no related grade 3–4 AEs. PK analysis revealed that indibulin plasma exposures increased approximately dose proportionally from 25 to 200 mg with Cmax of 165 ± 89 ng/mL and AUC0-24 of 1411 ± 111 ng·h/mL at 200 mg. There were no objective responses. Stable disease was seen in 1 pt in the 150 mg cohort. Longest duration on-study was 4 months. Conclusions: Oral indibulin was well tolerated in the doses up to 200 mg and the dose-proportional PK with lack of DLTs allows for further dose-escalation. Stable disease observed at sub-MTD dose may be a sign of activity in this heavily pre-treated population. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-11-10.

Introduction: This phase I/II study evaluated the safety and antitumor effect of the combination of erlotinib with cixutumumab, a recombinant fully humanized anti-insulin-like growth factor-1 receptor IgG1 monoclonal antibody, in advanced non-small cell lung cancer (NSCLC). Methods: Patients with advanced NSCLC were treated in an initial safety-lead and drop-down cohorts using erlotinib 150 mg/d with cixutumumab 6 or 5 mg/kg on days 1, 8, 15, and 22 in 28-day cycles (cohorts 1 and 2). Emerging pharmacokinetic data led to an additional cohort (3 + 3 design) with cixutumumab at 15 mg/kg on day 1 in 21-day cycles (cohort 3). Results: Eighteen patients entered the study (6 at 6 mg/kg, 8 at 5 mg/kg, and 4 at 15 mg/kg), with median age of 65 years. Four of six patients at 6 mg/kg experienced dose-limiting toxicities (DLTs), whereas at 5 mg/kg, one of eight patients experienced DLT but three of eight patients still required a dose delay during cycle 1. At 15 mg/kg every 21 days, two of four patients experienced DLTs. In all cohorts, DLTs were either G3 rash or fatigue. Five patients had stable disease as best response and 14 patients had progressive disease. The median progression-free survival was 39 days (range 21–432+ days). Biomarkers analyses showed a trend toward better progression-free survival seen with higher free baseline insulin-like growth factor-1 levels as seen with other insulin-like growth factor-1R inhibitors. Conclusions: The combinations of cixutumumab at 6 mg/kg every 7 days and 15 mg/kg every 21 days and full-dose erlotinib are not tolerable in unselected patients with NSCLC, as measured by DLT. Cixutumumab at 5 mg/kg every 7 days was tolerable per DLT, but dose delays were common. Efficacy in unselected patients with NSCLC seems to be low.

The purpose of this study was to assess the efficacy and safety of bevacizumab plus cetuximab with or without gemcitabine in patients with advanced pancreatic adenocarcinoma. Patients with locally advanced or metastatic pancreatic adenocarcinoma, previously untreated, were randomized to bevacizumab (10 mg/kg q2w) plus cetuximab (400/250 mg/m(2) initial/weekly), either with (Arm A) or without (Arm B) gemcitabine (1000 mg/m(2) weekly × 3 of 4 weeks). Tumor assessments were performed q8w. Primary study endpoint was progression-free survival (PFS). Sixty-one patients were randomized to Arm A (n = 30) or Arm B (n = 31). Median treatment duration was 9 weeks in Arm A and 8 weeks in Arm B (range, 2.0-40.4). Patients in Arm A had median PFS and overall survival values of 3.55 months and 5.41 months, respectively, compared to 1.91 months and 4.17 months in Arm B. The study closed early due to lack of sufficient efficacy in both treatment arms. Although both regimens were well tolerated, patients treated with gemcitabine experienced more grade 3-4 toxicities, including proteinuria and thromboembolic events. The combination of cetuximab and bevacizumab did not result in promising activity with or without gemcitabine, suggesting that a strategy of dual EGFR/VEGF inhibition in pancreatic cancer does not warrant further development. To our knowledge, this is one of the first trials to evaluate a completely noncytotoxic regimen in the first-line treatment of advanced pancreatic cancer. (ClinicalTrials.gov number, NCT00326911).

Importance Preferential delivery of docetaxel to tumors by prostate-specific membrane antigen (PSMA)–targeted nanoparticles is clinically effective, and the selective reduction of PSMA-positive circulating tumor cells (CTCs) after treatment has implications for patient selection and disease monitoring. Objective To determine the safety and efficacy of BIND-014, a PSMA-directed docetaxel-containing nanoparticle, in patients with metastatic castration-resistant prostate cancer (mCRPC). Design, Setting, and Participants A multicenter open-label, phase 2 clinical trial of 42 chemotherapy-naive patients with progressing mCRPC after treatment with abiraterone acetate and/or enzalutamide was conducted from June 24, 2013, to June 10, 2016. Intervention Treatment with BIND-014 at a dosage of 60 mg/m 2 was given intravenously on day 1 of 21-day cycles in combination with prednisone until disease progression or unacceptable toxic effects occurred. Main Outcomes and Measures The primary end point was radiographic progression-free survival according to Prostate Cancer Working Group 2 recommendations and Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included prostate-specific antigen (PSA) response (≥50% reduction from baseline) and changes in CTC number (from ≥5 to Results Among the 42 patients (81% white), the median age was 66 (range, 50-85) years, and median number of doses received was 6 (range, 1-21). A PSA response was observed in 12 of 40 patients (30%; 95% CI, 18%-45%), measurable disease response in 6 of 19 (32% [95% CI, 15%-54%]), and CTC conversions in 13 of 26 (50%; 95% CI, 32%-68%). Median radiographic progression-free survival was 9.9 (95% CI, 7.1-12.6) months. With use of the Epic Sciences non-EPCAM-based CTC detection platform, CTCs were detected in 16 of 18 patients (89%); 11 of 18 (61%) had CTCs with PSMA expression above the analytical threshold level (PSMA positive) at baseline (range, 0.4-72.4 CTCs/mL). After treatment, PSMA-positive CTCs were preferentially reduced. Treatment-related adverse events included grade 1 or 2 fatigue (29 of 42 patients [69%]), nausea (23 [55%]), neuropathy (14 [33%]), and neutropenic fever (1 [2%]). Conclusions and Relevance These findings suggest that treatment with BIND-014 is active and well tolerated in patients with chemotherapy-naive mCRPC. Antitumor activity may be related to PSMA expression levels on CTCs, which suggests that patients who are likely to benefit from this treatment can be identified before treatment is initiated. Trial Registration ClinicalTrials.gov Identifier:NCT01812746

TPS7590Background: Duvelisib is an oral dual inhibitor of phosphoinositide 3-kinase (PI3K)-δ and PI3K-γ being developed for the treatment of hematologic malignancies. In preclinical investigations,...

3086Background: Agenus AGEN2034 is a fully-human IgG4 monoclonal antibody antagonist targeting Programmed Cell Death Protein-1 (PD-1). The objective was to assess safety, MTD, pharmacokinetic (PK) ...

The human vascular endothelial growth factor receptor-1 (VEGFR-1, or Flt-1) is widely expressed in normal and pathologic tissue and contributes to the pathogenesis of both neoplastic and inflammatory diseases. In human cancer, VEGFR-1 mediated signaling is responsible for both direct tumor activation and angiogenesis. VEGFR-1 mediated activation of nonmalignant supporting cells, particularly stromal, dendritic, hematopoietic cells, and macrophages, is also likely important for cancer pathogenesis. VEGFR-1 is also hypothesized to enable the development of cancer metastases by means of activation and premetastatic localization in distant organs of bone marrow-derived hematopoietic progenitor cells, which express VEGFR-1. IMC-18F1 is a fully human IgG1 antibody that binds to VEGFR-1 and has been associated with the inhibition of cancer growth in multiple in vitro and human tumor xenograft models. The preliminary results of phase 1 investigations have also indicated a favorable safety profile for IMC-18F1 at doses that confer antibody concentrations that are associated with relevant antitumor activity in preclinical models. Cancer 2010;116(4 suppl):1027–32. © 2010 American Cancer Society.

FMS-related tyrosine kinase receptor 3 (FLT3) is a class III receptor tyrosine kinase that holds considerable promise as a therapeutic target in hematologic malignancies. Current efforts directed toward the development of small-molecule tyrosine kinase inhibitors of FLT3 may be limited by off-target toxicities and the development of drug resistance. Target-specific antibodies could overcome these hurdles and provide additional mechanisms to enhance the antitumor efficacy of FLT3 inhibitors. IMC-EB10 is a novel antibody directed against FLT3. The binding of IMC-EB10 to FLT3 results in antiproliferative effects in vitro and in mouse models engrafted with human leukemia cells that harbor wild-type or constitutively activated FLT3. Future clinical trials will test these notions formally and will identify the most appropriate opportunities for this member of a new generation of antileukemic therapies.

Summary Background Previous results from our phase 3 randomised trial showed that adding cetuximab to primary radiotherapy increased overall survival in patients with locoregionally advanced squamous-cell carcinoma of the head and neck (LASCCHN) at 3 years. Here we report the 5-year survival data, and investigate the relation between cetuximabinduced rash and survival. Methods Patients with LASCCHN of the oropharynx, hypopharynx, or larynx with measurable disease were randomly allocated in a 1:1 ratio to receive either comprehensive head and neck radiotherapy alone for 6–7 weeks or radiotherapy plus weekly doses of cetuximab: 400 mg/m² initial dose, followed by seven weekly doses at 250 mg/m². Randomisation was done with an adaptive minimisation technique to balance assignments across stratifi cation factors of Karnofsky performance score, T stage, N stage, and radiation fractionation. The trial was un-blinded. The primary endpoint was locoregional control, with a secondary endpoint of survival. Following discussions with the US Food and Drug Administration, the dataset was locked, except for queries to the sites about overall survival, before our previous report in 2006, so that an independent review could be done. Analyses were done on an intention-to-treat basis. Following completion of treatment, patients underwent physical examination and radiographic imaging every 4 months for 2 years, and then every 6 months thereafter . The trial is registered at www.ClinicalTrials.gov , number NCT00004227. Findings Patients were randomly assigned to receive radiotherapy with (n=211) or without (n=213) cetuximab, and all patients were followed for survival. Updated median overall survival for patients treated with cetuximab and radiotherapy was 49·0 months (95% CI 32·8–69·5) versus 29·3 months (20·6–41·4) in the radiotherapy-alone group (hazard ratio [HR] 0·73, 95% CI 0·56–0·95; p=0·018). 5-year overall survival was 45·6% in the cetuximab-plus-radiotherapy group and 36·4% in the radiotherapy-alone group. Additionally, for the patients treated with cetuximab, overall survival was signifi cantly improved in those who experienced an acneiform rash of at least grade 2 severity compared with patients with no rash or grade 1 rash (HR 0·49, 0·34–0·72; p=0·002). Interpretation For patients with LASCCHN, cetuximab plus radiotherapy signifi cantly improves overall survival at 5 years compared with radiotherapy alone, confi rming cetuximab plus radiotherapy as an important treatment option in this group of patients. Cetuximab-treated patients with prominent cetuximab-induced rash (grade 2 or above) have better survival than patients with no or grade 1 rash.

Purpose: First-in-human phase I trial to determine the safety, pharmacokinetics, and antitumor activity of BIND-014, a novel, tumor prostate-specific membrane antigen (PSMA)–targeted nanoparticle, containing docetaxel. Experimental Design: Patients with advanced solid tumors received BIND-014 every three weeks (n = 28) or weekly (n = 27), with dose levels ranging from 3.5 to 75 mg/m2 and 15 to 45 mg/m2, respectively. Results: BIND-014 was generally well tolerated, with no unexpected toxicities. The most common drug-related toxicities (>20% of patients) on either schedule included neutropenia, fatigue, anemia, alopecia, and diarrhea. BIND-014 demonstrated a dose-linear pharmacokinetic profile, distinct from docetaxel, with prolonged persistence of docetaxel-encapsulated circulating nanoparticles. Of the 52 patients evaluable for response, one had a complete response (cervical cancer on the every three week schedule) and five had partial responses (ampullary adenocarcinoma, non–small cell lung, and prostate cancers on the every-three-week schedule, and breast and gastroesophageal cancers on the weekly schedule). Responses were noted in both PSMA-detectable and -undetectable tumors. Conclusions: BIND-014 was generally well tolerated, with predictable and manageable toxicity and a unique pharmacokinetic profile compared with conventional docetaxel. Clinical activity was noted in multiple tumor types. The recommended phase II dose of BIND-014 is 60 mg/m2 every three weeks or 40 mg/m2 weekly. Clin Cancer Res; 22(13); 3157–63. ©2016 AACR.

Purpose: This phase II trial evaluated the efficacy and safety of cixutumumab, a human anti–insulin-like growth factor receptor 1 (IGF-1R) monoclonal IgG1 antibody, and explored potential biomarkers in postmenopausal women with hormone receptor–positive breast cancer. Experimental Design: Patients with hormone receptor–positive breast cancer that progressed on antiestrogen therapy received (2:1 randomization) cixutumumab 10 mg/kg and the same antiestrogen (arm A) or cixutumumab alone (arm B) every 2 weeks (q2w). Primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS) and safety. Correlative analyses of IGF-1R, total insulin receptor (IR), and IR isoforms A (IR-A) and B (IR-B) expression in tumor tissue were explored. Results: Ninety-three patients were randomized (arm A, n = 62; arm B, n = 31). Median PFS was 2.0 and 3.1 months for arm A and arm B, respectively. Secondary efficacy measures were similar between the arms. Overall, cixutumumab was well tolerated. IGF-1R expression was not associated with clinical outcomes. Regardless of the treatment, lower IR-A, IR-B, and total IR mRNA expression in tumor tissue was significantly associated with longer PFS [IR-A: HR, 2.62 (P = 0.0062); IR-B: HR, 2.21 (P = 0.0202); and total IR: HR, 2.18 (P = 0.0230)] and OS [IR-A: HR, 2.94 (P = 0.0156); IR-B: HR, 2.69 (P = 0.0245); and total IR: HR, 2.72 (P = 0.0231)]. Conclusions: Cixutumumab (10 mg/kg) with or without antiestrogen q2w had an acceptable safety profile, but no significant clinical efficacy. Patients with low total IR, IR-A, and IR-B mRNA expression levels had significantly longer PFS and OS, independent of the treatment. The prognostic or predictive value of IR as a biomarker for IGF-1R–targeted therapies requires further validation. Clin Cancer Res; 22(2); 301–9. ©2015 AACR.

Radioactive ligands for the prostate-specific membrane antigen (PSMA) are under development for therapy of metastasized prostate cancer. Since PSMA expression is also found in the kidneys, renal tracer uptake can be dose-limiting. Because kidney kinetics differ from tumor kinetics, serial application of PSMA inhibitors such as 2-(phosphonomethyl)pentanedioic acid (PMPA) may improve the kidney-to-tumor ratio. In this study, we evaluated the effect of PMPA on the biodistribution of 2 promising PSMA ligands. Methods: Human prostate cancer xenografts (LNCaP) were transplanted subcutaneously into mice. After injection of 125I-MIP1095, a 16-h latency period was allowed for tracer clearance from the blood and renal calices. After baseline scintigraphy, PMPA was injected in doses of 0.2–50 mg/kg (n = 3 per dose, 5 controls), followed by scans at 2, 4, 6, and 24 h after PMPA injection. Kidney and tumor displacement was determined as a percentage of baseline. A shortened but similar design was used to evaluate the PSMA ligand MIP1404, which contains a chelate for 99mTc/rhenium. Results: PMPA injection 16 h after MIP1095 translated into a rapid and quantitative relevant displacement of renal activity. Tumor uptake was reduced to a significantly lesser extent in a dose-dependent manner. PMPA doses of 0.2–1 mg/kg appear optimal for sustaining nearly complete tumor uptake while simultaneously achieving near-total blocking of specific renal PSMA binding. The effect was successfully validated with the PSMA ligand MIP1404. Conclusion: PSMA-targeted radionuclide therapy can benefit from serial PMPA comedication by reducing off-target radiation to the kidneys. These data will be used for a first approximation in clinical translation, although in patients an optimization of the dose and time schedule may be necessary.

BACKGROUND We conducted a multinational, randomized study to compare radiotherapy alone with radiotherapy plus cetuximab, a monoclonal antibody against the epidermal growth factor receptor, in the treatment of locoregionally advanced squamous-cell carcinoma of the head and neck. METHODS Patients with locoregionally advanced head and neck cancer were randomly assigned to treatment with high-dose radiotherapy alone (213 patients) or high-dose radiotherapy plus weekly cetuximab (211 patients) at an initial dose of 400 mg per square meter of body-surface area, followed by 250 mg per square meter weekly for the duration of radiotherapy. The primary end point was the duration of control of locoregional disease; secondary end points were overall survival, progression-free survival, the response rate, and safety. RESULTS The median duration of locoregional control was 24.4 months among patients treated with cetuximab plus radiotherapy and 14.9 months among those given radiotherapy alone (hazard ratio for locoregional progression or death, 0.68; P = 0.005). With a median follow-up of 54.0 months, the median duration of overall survival was 49.0 months among patients treated with combined therapy and 29.3 months among those treated with radiotherapy alone (hazard ratio for death, 0.74; P = 0.03). Radiotherapy plus cetuximab significantly prolonged progression-free survival (hazard ratio for disease progression or death, 0.70; P = 0.006). With the exception of acneiform rash and infusion reactions, the incidence of grade 3 or greater toxic effects, including mucositis, did not differ significantly between the two groups. CONCLUSIONS Treatment of locoregionally advanced head and neck cancer with concomitant highdose radiotherapy plus cetuximab improves locoregional control and reduces mortality without increasing the common toxic effects associated with radiotherapy to the head and neck. (ClinicalTrials.gov number, NCT00004227.)

Background Cixutumumab (IMC-A12), a fully human immunoglobulin G1 (IgG1) monoclonal antibody, exerts preclinical activity in several sarcoma models and may be effective for the treatment of these tumours. Methods In this open-label, multicentre, phase 2 study, patients with previously treated advanced or metastatic rhabdomyosarcoma, leiomyosarcoma, adipocytic sarcoma, synovial sarcoma or Ewing family of tumours received intravenous cixutumumab (10 mg/kg) for 1 h every other week until disease progression or discontinuation. The primary end-point was the progression-free survival rate (PFR), defined as stable disease or better at 12 weeks. In each tier of disease histology, Simon's optimum 2-stage design was applied (PFR at 12 weeks P0 = 20%, P1 = 40%, α = 0.10, β = 0.10). Stage 1 enrolled 17 patients in each disease group/tier, with at least four patients with stable disease or better required at 12 weeks to proceed to stage 2. Results A total of 113 patients were enrolled; all tiers except adipocytic sarcoma were closed after stage 1 due to futility. The 12-week PFR was 12% for rhabdomyosarcoma (n = 17), 14% for leiomyosarcoma (n = 22), 32% for adipocytic sarcoma (n = 37), 18% for synovial sarcoma (n = 17) and 11% for Ewing family of tumours (n = 18). Median progression-free survival (weeks) was 6.1 for rhabdomyosarcoma, 6.0 for leiomyosarcoma, 12.1 for adipocytic sarcoma, 6.4 for synovial sarcoma and 6.4 for Ewing family of tumours. Among all patients, the most frequent treatment-emergent adverse events (AEs) were nausea (26%), fatigue (23%), diarrhoea (23%) and hyperglycaemia (20%). Conclusions Patients with adipocytic sarcoma may benefit from treatment with cixutumumab. Cixutumumab treatment was well tolerated, with limited gastrointestinal AEs, fatigue and hyperglycaemia. © 2013 Elsevier Ltd. All rights reserved.

Background IMC-18F1 (icrucumab), a human monoclonal antibody against vascular endothelial growth factor receptor-1 (VEGFR-1), potently inhibits ligand-dependent phosphorylation of VEGFR-1 and downstream signaling, making icrucumab an attractive candidate for antitumor activity. Objectives The primary objective was to determine the safety profile and maximum tolerated dose of icrucumab in patients with advanced solid tumors that were previously unresponsive to standard therapy or for which no standard therapy was available. Methods In this open-label, dose-escalation, Phase 1 study, patients received icrucumab intravenously weekly at 2, 3, 6, and 12 mg/kg (Cohorts 1–4), every other week (q2w) at 15 mg/kg (Cohort 5), or every third week at 20 mg/kg (Cohort 6). Patients received icrucumab until evidence of progressive disease or other withdrawal criteria were met. Results Twenty-six patients received icrucumab. The most common adverse events were fatigue, nausea, peripheral edema, anemia, dyspnea, and vomiting. No dose-limiting toxicities (DLTs) were observed in Cohorts 1–5. Two DLTs were observed in Cohort 6 (anemia and hyponatremia), and enrollment was stopped. No patient demonstrated an immunogenic response. Overall, icrucumab exhibited nonlinear pharmacokinetics at doses >6 mg/kg. Six patients (23.1 %) achieved stable disease with median duration of 11.1 weeks (range = 10.3–18.7 weeks); tumor types were thyroid, melanoma, colorectal (3 patients), and small-cell lung cancers. Conclusions Icrucumab was safely administered weekly at doses of 2–12 mg/kg and q2w at a dose of 15 mg/kg with no DLTs. Based on achievement of stable disease, icrucumab has potential for antitumor activity against advanced solid tumors.

233 Background: BIND-014 is a novel PSMA-targeted Accurin (polymeric nanoparticle) that contains docetaxel (D). BIND-014 is anticipated to improve the therapeutic index of D by increasing its intratumoral concentration and duration of exposure. In a phase 1 study, BIND-014 was generally well-tolerated and displayed anti-tumor effects, including in two patients with chemotherapy-naïve mCRPC. Methods: A phase 2 study was conducted of BIND-014 administered by a 60-min IV infusion at 60 mg/m² on day 1 of a 21-day cycle in combination with 5 mg of prednisone twice per day to patients with chemotherapy-naïve mCRPC. Prior treatment included abiraterone acetate (AA, 48%), enzalutamide (E, 12%) or both (14%). Of these 31 patients 19% progressed within ≤ 6 months on prior AA and/or E. The primary endpoint was radiographic progression-free survival (rPFS) using PCWG2 for bone and RECIST v1.1. Other endpoints included prostate specific antigen (PSA) and circulating tumor cell count (CTC) conversions, objective response rate (ORR), and overall survival (OS). Results: Forty-two patients were enrolled and received a median of 6 doses (range 1 – 21). Median rPFS was 7.1 months (95% CI: 2.6 – 9.9) with 4 patients (10%) censored. PSA response ( ≥ 50% reduction from baseline) was observed in 12 of 40 patients (30%). CTC conversions (from ≥ 5 CTCs/7.5 mL of blood at baseline to < 5 CTCs) occurred in 13 of 26 patients (50%). ORR was 32% with 3 confirmed responses (1 complete response and 2 partial responses) and 3 unconfirmed responses out of 19 patients with measurable disease. Estimated median OS was 13.4 months (95% CI: 9.9 – 18.6) with 14 patients (33%) censored. The most common hematological treatment-related adverse events (TRAEs) observed were lymphopenia (26%), and anemia (19%).Fatigue (69%), nausea (55%), diarrhea (45%), dyspnea (36%), and neuropathy (33%) were the most common non-hematological TRAEs. The most common TRAEs were generally grade 1 and 2. Conclusions: BIND-014 administered at 60 mg/m² on day 1 of a 21-day cycle is clinically active and well-tolerated when administered to patients with chemotherapy-naïve mCRPC including those with prior AA and/or E. Clinical trial information: NCT01812746.

Purpose: This study aimed to determine a maximum tolerated dose (MTD) and recommended dose for disease-directed studies of necitumumab (IMC-11F8), a fully human IgG1 monoclonal antibody directed at the epidermal growth factor receptor, and to characterize the safety profile, pharmacokinetics, preliminary antitumor activity, and immunogenicity of necitumumab. Experimental Design: Patients with advanced solid malignancies were treated with 100 to 1,000 mg (flat dosing) necitumumab followed by a 2-week pharmacokinetics sampling period, before beginning 6-week cycles of therapy. Results: Sixty patients received necitumumab weekly (29 patients) or every other week (31 patients). Two patients receiving 1,000 mg every 2 weeks experienced dose-limiting toxicities (DLT; grade 3 headache), accompanied by grade 3 nausea and vomiting in one patient. Occurring hours after the initial dose, these DLTs established 800 mg as the MTD. Mild dose-related skin toxicity was the most common drug-related toxicity (80%). One patient in each arm experienced grade 3 acneform rash, which responded to oral antibiotics and topical therapy. Toxicity was similar on both schedules. Necitumumab exhibited saturable elimination and nonlinear pharmacokinetics. At 800 mg (both arms), its half-life was approximately 7 days. All patients treated with ≥600 mg necitumumab achieved target trough concentrations (≥40 μg/mL). Antibodies against necitumumab were not detected. Partial response and stable disease were experienced by 2 and 16 patients, respectively. Conclusion: Well tolerated, necitumumab is associated with preliminary evidence of antitumor activity, and achieves biologically relevant concentrations throughout the dosing period. The recommended dose of necitumumab for further clinical development is 800 mg (flat dose) weekly or every 2 weeks based on the clinical setting. Clin Cancer Res; 16(6); 1915–23

Purpose To evaluate the safety, maximum-tolerated dose (MTD), pharmacokinetics (PKs), pharmacodynamics, and preliminary anticancer activity of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor (VEGFR)-2. Patients and Methods Patients with advanced solid malignancies were treated once weekly with escalating doses of ramucirumab. Blood was sampled for PK studies throughout treatment. The effects of ramucirumab on circulating vascular endothelial growth factor-A (VEGF-A), soluble VEGFR-1 and VEGFR-2, tumor perfusion, and vascularity using dynamic contrast-enhanced magnetic resonance imaging were assessed. Results Thirty-seven patients were treated with 2 to 16 mg/kg of ramucirumab. After one patient each developed dose-limiting hypertension and deep venous thrombosis at 16 mg/kg, the next lower dose (13 mg/kg) was considered the MTD. Nausea, vomiting, headache, fatigue, and proteinuria were also noted. Four (15%) of 27 patients with measurable disease had a partial response (PR), and 11 (30%) of 37 patients had either a PR or stable disease lasting at least 6 months. PKs were characterized by dose-dependent elimination and nonlinear exposure consistent with saturable clearance. Mean trough concentrations exceeded biologically relevant target levels throughout treatment at all dose levels. Serum VEGF-A increased 1.5 to 3.5 times above pretreatment values and remained in this range throughout treatment at all dose levels. Tumor perfusion and vascularity decreased in 69% of evaluable patients. Conclusion Objective antitumor activity and antiangiogenic effects were observed over a wide range of dose levels, suggesting that ramucirumab may have a favorable therapeutic index in treating malignancies amenable to VEGFR-2 inhibition.

In this multinational, placebo-controlled, randomized phase III trial, Translational Research In Oncology (TRIO) will define the efficacy and safety of adding a novel antiangiogenic agent, IMC-1121B (ramucirumab), to standard first-line docetaxel chemotherapy for women with HER2-negative metastatic breast cancer. We will evaluate whether the addition of IMC-1121B prolongs progression-free survival and whether its use improves overall survival. Accrual is under way.

Purpose To determine antitumor activity of cetuximab monotherapy in patients with refractory metastatic colorectal carcinoma (mCRC) with lack of specific membrane immunostaining for the epidermal growth factor receptor (EGFR). Patients and methods Patients had immunohistochemical (IHC)-determined mCRC with absent EGFR immunostaining that progressed after receiving at least one standard, fluoropyrimidine-containing chemotherapeutic regimen. Absent EGFR immunostaining was defined as the IHC absence of specific membrane staining in ≥500 cancer cells examined in well-preserved tissue. The study was performed prior to results of studies linking cetuximab sensitivity to K-ras mutation status. Patients received 400 mg/m2 of intravenous (i.v.) cetuximab followed by once-weekly i.v. cetuximab 250 mg/m2 until disease progression or unacceptable toxicity. Patients were evaluated for objective response at least every 6 weeks. Kaplan-Meier estimates were calculated for duration of response, time to progression (TTP), and overall survival (OS). Results Seven (8.2%) of 85 mCRC patients whose tumors lacked EGFR immunostaining had major responses following cetuximab treatment. The median duration of response was 5.1 months. Median TTP and OS were 2.5 months and 10.0 months, respectively; the 1-year survival rate was 39.6%. The most frequently reported cetuximab-related adverse events were acneiform dermatitis, fatigue, headache, and dry skin. Conclusion Cetuximab monotherapy produces objective antitumor activity in patients with mCRC that does not express EGFR as determined by IHC. The activity and safety profiles of cetuximab monotherapy in mCRC lacking EGFR immunostaining are similar to previous observations in EGFR IHC-positive disease that was not selected based on K-ras mutation status.

Angiogenesis is a fundamental mechanism of cancer growth and invasion. Current translational approaches are using both small-molecule inhibitors and antibodies that modulate various steps of these processes, and several such compounds have already received regulatory approval for the therapy of specific indications in cancer. Among the many molecular targets involved in the control of angiogenesis, the vascular endothelial growth factor receptor-2 (VEGFR-2; or kinase insert domain-containing receptor) is attractive as shown in part by the efficacy of small-molecule inhibitors directed to this receptor. Two small-molecule inhibitors that target VEGFR-2 have recently been granted approval for the treatment of renal cell cancer and gastrointestinal stromal tumors. The development of antibodies that can selectively block VEGFR-2 could potentially result in improved potency or tolerability. Here, we discuss the role of VEGFR-2 in cancer and ongoing efforts to develop highly specific monoclonal antibodies for cancer therapy.

The authors of this Viewpoint argue there are no facile solutions to replace the painstaking, empirical effort required to identify the targets within 'addicted' tumors. Redundant pathways and our incomplete understanding of drug targets cast doubt on biomarker evidence unless reinforced by biological observations. Further integration of academia, industry and the regulatory organizations is required.