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Purpose: The PARP inhibitor (PARPi) talazoparib may potentiate activity of chemotherapy and toxicity in cells vulnerable to DNA damage.Experimental Design: This phase I study evaluated the safety, tolerability, pharmacokinetics, and efficacy of talazoparib and carboplatin. Pharmacokinetic modeling explored associations between DNA vulnerability and hematologic toxicity.Results: Twenty-four patients (eight males; 16 females) with solid tumors were enrolled in four cohorts at 0.75 and 1 mg daily talazoparib and weekly carboplatin (AUC 1 and 1.5, every 2 weeks or every 3 weeks), including 14 patients (58%) with prior platinum treatment. Dose-limiting toxicities included grade 3 fatigue and grade 4 thrombocytopenia; the MTD was not reached. Grade 3/4 toxicities included fatigue (13%), neutropenia (63%), thrombocytopenia (29%), and anemia (38%). After cycle 2's dose, delays/reductions were required in all patients. One complete and two partial responses occurred in germline BRCA1/2 (gBRCA1/2) patients. Four patients showed stable disease beyond 4 months, three of which had known mutations in DNA repair pathways. Pharmacokinetic toxicity modeling suggests that after three cycles of carboplatin AUC 1.5 every 3 weeks and talazoparib 1 mg daily, neutrophil counts decreased 78% [confidence interval (CI), 87–68] from baseline in gBRCA carriers and 63% (CI, 72–55) in noncarriers (P < 0.001). Pharmacokinetic toxicity modeling suggests an intermittent, pulse dosing schedule of PARP inhibition, differentiated by gBRCA mutation status, may improve the benefit/risk ratio of combination therapy.Conclusions: Carboplatin and talazoparib showed efficacy in DNA damage mutation carriers, but hematologic toxicity was more pronounced in gBRCA carriers. Carboplatin is best combined with intermittent talazoparib dosing differentiated by germline and somatic DNA damage mutation carriers. Clin Cancer Res; 23(21); 6400–10. ©2017 AACR.

Supplementary table 1 Observed and predicted blood toxicity profile at the start of Cycle 2 and Cycle 4 (A) and PK-toxicity model-predicted (B) neutrophil and platelet toxicity at cycle 2, day 1 and cycle 5 talozaparib 1mg/carboplatin AUC 1/5 weekly dosing: Absolute change from baseline. Supplementary Table 2: PK toxicity model estimates Supplementary Figure 1a: Goodness of fit plots of all modeled PK and PK-toxicity data. Supplementary Figure 2 Talazoparib drug clearance in gBRCA carriers versus non-carriers of talazoparib Supplementary table 3 Simulated blood toxicity profile of new dosing regimens using the PK-toxicity model. A) planned schedule B) optimized talazoparib, C) optimized carboplatin, D) optimized combination E) simulation of single agent toxicity.

Background: BRCA1 and BRCA2 are key mediators of DNA damage repair response including the homologous recombination repair (HRR) pathway. Mutations in these genes predispose women to various cancers including breast, ovarian and pancreatic cancers. A new class of drugs, the poly (ADP-ribose) polymerase inhibitors (PARPi), were designed to leverage impaired DNA repair in BRCA-mutated tumors and are FDA approved for various cancers (breast, ovarian). Efforts to combine PARPi with cytotoxic agents show increased efficacy but overlapping toxicities hamper their tolerability. Further, the short duration of response to PARPi monotherapy in diseases like breast cancer has inspired the search for PARPi combinations with other agents including epigenetic modifiers. To overcome these hurdles, we explored synergistic interactions between PARPi and DNA methyltransferases inhibitors (DNMTi) such as decitabine, a cytidine analog. When incorporated in newly synthesized DNA strands during S phase, these agents will trigger a covalent protein-DNA complex formation causing cell cycle arrest and cell death. Material & Methods: BRCA wild-type (WT) and BRCA-mutated breast cancer cell lines were used for in vitro analyses: SUM149PT and HCC-3153 (BRCA1-mutated), MDA-MB-231 and BT-549 (BRCA-WT), UCRP231A (a CRISPR/Cas9 engineered BRCA2-mutated from parental MDA-MB-231), and MCF10A (a BRCA-WT non-tumorigenic breast cell line). The combined effect of talazoparib (PARPi) and decitabine (DNMTi) was analyzed using Combenefit® software to determine their synergistic interaction. Cell cycle analyses, dead/alive cells ratio analyses, as well as pH2AX levels were evaluated. In vivo analyses included xenograft models with SUM149PT as well as the parental BRCA-WT MDA-MB-231 and BRCA2-mutated MDA-MB-231 (UCRP231A) cells in immunodeficient NOD.Cg-Rag1tm1Mom Il2rgtm1Wjl/SzJ mice. Results: Our preclinical data in BRCA-deficient breast cancer cell lines, demonstrated a synergistic inhibition of cell growth and enhancement of cell death at concentrations of talazoparib and decitabine where each agent individually had minimal efficacy. In cells with intact HRR pathways, the drug combination showed an enhanced inhibition of cell growth but was not synergistic in inducing cell death compared to BRCA deficient cell lines. This difference was further manifested by different cell cycle profiles: non-BRCA mutated cells arrested in S-phase while BRCA-mutated cells progressed through S-phase without arrest and entered cell death from G2/M. In vivo mouse data showed a significant synergistic interaction between the two drugs without enhanced toxicity. Conclusion: The ability to induce a synergistic interaction between talazoparib and decitabine at low drug concentrations present a promising therapeutic strategy for patients with HRR-deficient tumors. Ongoing experiments are being conducted to generate additional engineered BRCA- and other HRR-deficient cell lines (ATM, CHEK2 and others) through CRISPR/Cas9 DNA editing system and further delineate the differential mechanism of interaction between the HRR-deficient and HRR-intact cell lines in preparation for clinical testing. Citation Format: Romain Pacaud, Mallika Dhawan, Scott Thomas, Elysia Roche, Jose Garcia, Nela Pawlowska, Pamela Munster. Epigenetic modulation to deepen and prolong the response to PARP inhibitors [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 P3-11-12.

This abstract was not presented at the conference. Citation Format: Pacaud R, Thomas S, Roche E, Pawlowska N, Munster P. Not presented [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-21-10.

3150 Background: Histone deacetylase (HDAC) inhibition downregulates HIF-1a, which may be effective in overcoming resistance to VEGF-targeting tyrosine kinase inhibitors. We report the updated survival follow-up for patients treated with abexinostat and pazopanib in a phase Ib trial. Methods: Patients with solid tumor malignancies were enrolled in this phase Ib, open-label trial (NCT01543763) of abexinostat in combination with pazopanib (3+3 design), with a dose expansion restricted to renal cell carcinoma (RCC). Patients received a 1-week run-in period with abexinostat alone, and then combination abexinostat with pazopanib during a 28-day treatment cycle until disease progression, unacceptable toxicity or study withdrawal. Plasma samples from 29 patients were sent for metabolomics analysis. Results: 51 patients were enrolled: N = 36 patients in dose escalation, N = 15 in dose expansion. At the time of last report in 2017, 5 patients remained on study treatment: N = 4 with RCC, and N = 1 with thymic neuroendocrine carcinoma. 4 of these patients have now had disease progression. Median duration of therapy measured 44.9 months (range 39.8-102.2). One patient with metastatic RCC (patient 1) remains on study treatment, after progression on 5 prior lines of systemic therapy. With updated survival follow-up, median OS measured 12.4 months in the dose escalation arm and 27.65 months in the RCC dose expansion cohort. Overall median duration of therapy in all 51 patients measured 5.6 months (range 1-103 months). Progression-free survival among patients with high PBMC HDAC2 expression (> 0.4) remains longer compared to those with low expression (median 6.3 vs. 3.7 months, p = 0.0041). Metabolomics analysis demonstrated a negative correlation between HDAC2 and N6-acetyllysine, suggesting that baseline HDAC2 may impact efficacy of HDAC inhibition. Conclusions: The combination of abexinostat with pazopanib appears promising, with the potential for long-term responses particularly in patients with metastatic RCC. This has led to an ongoing phase III trial examining this combination in RCC. Clinical trial information: NCT01543763. [Table: see text]

3001 Background: FOR46, a fully human antibody (ab) conjugated to monomethyl auristatin E (MMAE), targets a tumor selective epitope of CD46, which is highly expressed in mCRPC and treatment-emergent small cell neuroendocrine cancer (t-SCNC). CD46 is enriched in tumor cells upon treatment with androgen signaling inhibitors (ASI). Following dose escalation (Phase 1a), dose expansion was undertaken in 2 cohorts (Phase 1b): 1) Pts with de novo or t-SCNC and 2) pts with mCRPC without a t-SCNC component. Pts with adenocarcinoma enrolled in dose escalation and expansion are included in this analysis. Methods: Eligible pts had mCRPC, with progression on at least 1 ASI, with no prior chemotherapy for CRPC. Phase 1a pts received FOR46 0.1-3.0 mg/kg IV Q3 weeks (wks). The primary objectives in phase 1a were to assess adverse effects (AEs) and select the phase 1b dose; and in phase 1b to assess efficacy. For phase 1b, tumor biopsy in the CRPC setting for assignment to the 2 cohorts was required. CD46 expression was not required for inclusion in the expansion cohort, but was evaluated using a non-epitope specific CD46 polyclonal ab. Histology and CD46 expression were centrally reviewed. Results: Thirty-three pts were enrolled in phase 1a and 10 in phase 1b (including 6 treated in ph1a at the expansion dose or higher). Overall, 36 pts were treated at doses > 1.2 mg/kg. Following excess toxicity in pts with body mass indices > 30 (3 of 3 with Gr 4 neutropenia and 1 of 3 with Gr 3 fatigue at 2.4 mg/kg), further dosing was calculated using adjusted body weight (AJBW) rather than actual weight, allowing escalation to 3.0 mg/kg. The 2.7 mg/kg dose by AJBW was determined to be the MTD and phase 1b dose. The most common AEs at the 2.7 mg/kg dose were neutropenia (77% Gr 3 or 4), infusion reactions (37%, all < Gr 2), fatigue (31%, all < Gr 2) and peripheral neuropathy (24%, all < Gr 2)). Fourteen of 31 evaluable pts (45.2%) at > 1.2 mg/kg achieved a PSA50 response with 10 (32.3%) confirmed. Five pts were not evaluable for PSA response; 3 had no post-baseline PSA and 2 had baseline PSA < 1 ng/mL. The median duration of confirmed PSA50 response is >16 wks (range 6-48+ wks, with 4 ongoing at 12, 24, 25 and 48 wks). 18 pts had measurable lesions; 8 of 18 (44.4%) had tumor regression, with 4 (22.2%) confirmed partial responses (PR). The median duration of response is > 14 wks (range 9 -31+ weeks with 2 ongoing at 13 and 31 wks). Eight pts were evaluable for CD46 expression with a median H-score of 245 (range 0-300). Two pts with PRs had H-scores of 15 and 300; 4 with confirmed PSA50 had H-scores of 10, 15, 40 and 300. Conclusions: FOR46, a novel ADC targeting CD46, demonstrates clinical activity in mCRPC pts, with an acceptable safety profile, similar to other MMAE-containing ADCs. FOR46 merits further investigation in pts with mCRPC, alone and in combination with agents that enhance CD46 expression. Clinical trial information: NCT03575819.

Most cancer treatment and prevention strategies include removal of the respective organ or systemic therapy. Early interception and cancer prevention is fraught with uncertainties in individual risk assessment and the absence of early surrogate markers to monitor efficacy. Hence, cancer prevention studies typically require large patient numbers. They are performed in unselected populations without clearly defined risk and benefits are often small or diluted. Hence, even successful strategies with documented benefit such as tamoxifen, have found only poor uptake in the at-risk population. Many women and providers are deterred by the low benefits to risk ratio of systemic tamoxifen exposure. The opportunity to selectively treat with an effective agent would limit the need for surgery and circumvent systemic exposure. We propose a less toxic and less debilitating approach to prevent and treat early stage breast cancer by utilizing the slow release of anti-estrogens from silastic tubing as a local drug delivery device to the breast. Our in vitro and in vivo data demonstrate consistent release of active fulvestrant through at least 52 weeks. Extrapolating from the amount of residual drug left in the tubing after 52 weeks suggests that drug release could be maintained sufficiently to and beyond 5 years. Silastic tubing released fulvestrant at clinically relevant concentrations and associated with inhibition of ER signaling and cell proliferation in vitro. In vivo anti-tumor activity was comparable to systemic administration of the anti-estrogen. The silastic tubing preferentially delivered the anti-estrogen to mammary tissue with minimal accumulation in major organs and 20-fold lower concentrations in adjacent (abdominal) and distant fat (thoracic) pads. Consistent with fulvestrant penetrance through tumors, local delivery was more effective in reducing Ki-67 immediately adjacent to the tubing but maintained concentrations comparable to systemic therapy throughout the entire tumors. We further demonstrated that human fat cells readily take up fulvestrant and then transfer the drug to breast cancer cells. These findings support the use of local drug delivery through the human breast tissue and surrounding fatty tissue. Mammary tissues are rapidly cleared of fulvestrant upon removal of the drug-loaded tubing. This would allow the long term implantation of a drug delivery device designed to be emptied or refilled. Local drug delivery is ideally suited in a setting of local disease or recurrence with minimal risk for systemic metastases with the goal of producing high concentrations without systemic application of the drug. Our data support the concept of a local silastic tubing device as a means to locally deliver an anti-estrogen in three major applications: early interventions for localized tumors, such as ductal carcinoma in situ (DCIS) or early stage breast cancer with low metastatic potential, prevention of breast cancer in women at higher risk due genetic predisposition, or used in concert with systemic therapy to provide a localized therapeutic boost. Overall, the use of implantable silastic tubing for local drug delivery represents a promising approach and introduces a potential paradigm shift in prevention and treatment of breast cancer. Citation Format: Munster PN, Park J, Desai P, Garcia E, Cheng S, Greier S, Pawlowska N, Chaudhuri AR, Thomas S. A novel implant to deliver localized hormonal therapy to prevent and treat breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-14-04.

Triple-negative breast cancer (TNBC) represents a more aggressive and difficult subtype of breast cancer where responses to chemotherapy occur, but toxicity is significant and resistance often follows. Immunotherapy has shown promising results in various types of cancer, including breast cancer. Here, we investigated a new combination strategy where histone deacetylase inhibitors (HDACi) are applied with immune checkpoint inhibitors to improve immunotherapy responses in TNBC. Testing different epigenetic modifiers, we focused on the mechanisms underlying HDACi as priming modulators of immunotherapy. Tumor cells were co-cultured with human peripheral blood mononuclear cells (PBMCs) and flow cytometric immunophenotyping was performed to define the role of epigenetic priming in promoting tumor antigen presentation and immune cell activation. We found that HDACi up-regulate PD-L1 mRNA and protein expression in a time-dependent manner in TNBC cells, but not in hormone responsive cells. Focusing on TNBC, HDACi up-regulated PD-L1 and HLA-DR on tumor cells when co-cultured with PBMCs and down-regulated CD4+ Foxp3+ Treg in vitro. HDACi significantly enhanced the in vivo response to PD-1/CTLA-4 blockade in the triple-negative 4T1 breast cancer mouse model, the only currently available experimental system with functional resemblance to human TNBC. This resulted in a significant decrease in tumor growth and increased survival, associated with increased T cell tumor infiltration and a reduction in CD4+ Foxp3+ T cells in the tumor microenvironment. Overall, our results suggest a novel role for HDAC inhibition in combination with immune checkpoint inhibitors and identify a promising therapeutic strategy, supporting its further clinical evaluation for TNBC treatment.

Purpose: The histone deacetylase (HDAC) inhibitor panobinostat potentiates anthracycline and cytarabine cytotoxicity in acute myeloid leukemia (AML) cells. We hypothesized that panobinostat prior to and during induction chemotherapy would be tolerable and augment response in patients showing increased histone acetylation. Patients and Methods: Patients received panobinostat 20–60 mg oral daily on days 1, 3, 5, and 8 with daunorubicin 60 mg/m2/day intravenously on days 3 to 5 and cytarabine 100 mg/m2/day intravenously by continuous infusion on days 3 to 9 (“7+3”). Peripheral blood mononuclear cells (PBMCs) were isolated for HDAC expression and histone acetylation changes. Results: Twenty-five patients ages 60–85 years (median age, 69) were treated. Fifteen patients had de novo AML, six AML with myelodysplasia-related changes, two AML with prior myeloproliferative neoplasm, one therapy-related myeloid neoplasm, and one myelodysplastic syndrome with excess blasts-2. No dose-limiting toxicities occurred in dose escalation cohorts. In dose expansion, six patients received panobinostat at 60 mg and nine patients at 50 mg due to recurrent grade 1 bradycardia at the 60-mg dose. The complete response (CR)/incomplete count recovery (Cri) rate was 32%. Median overall survival was 10 months: 23 months with CR/CRi versus 7.8 months without CR/CRi (log-rank P = 0.02). Median relapse-free survival was 8.2 months. Increased histone acetylation 4 and 24 hours after panobinostat was significantly associated with CR/CRi. Conclusions: Panobinostat with “7+3” for older patients with AML was well tolerated. Panobinostat 50 mg on days 1, 3, 5, and 8 starting 2 days prior to “7+3” is recommended for future studies. Panobinostat-induced increases in histone acetylation in PBMCs predicted CR/CRi.

Broad use of germline testing has identified an increasing number of women at risk for breast cancer with a need for effective chemoprevention. We report a novel method to selectively deliver various anti-estrogens at high drug levels to the breast tissue by implanting a device comprised of silastic tubing. Optimized tubing properties allow elution of otherwise poorly bioavailable anti-estrogens, such as fulvestrant, into mammary tissue in vitro and in vivo with levels sufficient to inhibit estrogen receptor activation and tumor cell proliferation. Implantable silastic tubing delivers fulvestrant selectively to mouse mammary fat tissue for one year with anti-tumor effects similar to those achieved with systemic fulvestrant exposure. Furthermore, local delivery of fulvestrant significantly decreases cell proliferation, as assessed by Ki67 expression, most effectively in tumor sections adjacent to tubing. This approach may thereby introduce a potential paradigm shift and offer a promising alternative to systemic therapy for prevention and early interception of breast cancer.

Purpose: The PARP inhibitor (PARPi) talazoparib may potentiate activity of chemotherapy and toxicity in cells vulnerable to DNA damage. Experimental Design: This phase I study evaluated the safety, tolerability, pharmacokinetics, and efficacy of talazoparib and carboplatin. Pharmacokinetic modeling explored associations between DNA vulnerability and hematologic toxicity. Results: Twenty-four patients (eight males; 16 females) with solid tumors were enrolled in four cohorts at 0.75 and 1 mg daily talazoparib and weekly carboplatin (AUC 1 and 1.5, every 2 weeks or every 3 weeks), including 14 patients (58%) with prior platinum treatment. Dose-limiting toxicities included grade 3 fatigue and grade 4 thrombocytopenia; the MTD was not reached. Grade 3/4 toxicities included fatigue (13%), neutropenia (63%), thrombocytopenia (29%), and anemia (38%). After cycle 2's dose, delays/reductions were required in all patients. One complete and two partial responses occurred in germline BRCA1/2 (gBRCA1/2) patients. Four patients showed stable disease beyond 4 months, three of which had known mutations in DNA repair pathways. Pharmacokinetic toxicity modeling suggests that after three cycles of carboplatin AUC 1.5 every 3 weeks and talazoparib 1 mg daily, neutrophil counts decreased 78% [confidence interval (CI), 87–68] from baseline in gBRCA carriers and 63% (CI, 72–55) in noncarriers (P < 0.001). Pharmacokinetic toxicity modeling suggests an intermittent, pulse dosing schedule of PARP inhibition, differentiated by gBRCA mutation status, may improve the benefit/risk ratio of combination therapy. Conclusions: Carboplatin and talazoparib showed efficacy in DNA damage mutation carriers, but hematologic toxicity was more pronounced in gBRCA carriers. Carboplatin is best combined with intermittent talazoparib dosing differentiated by germline and somatic DNA damage mutation carriers. Clin Cancer Res; 23(21); 6400–10. ©2017 AACR.

Background Poly(ADP-ribose) polymerase inhibitors (PARPi), coupled to a DNA damaging agent is a promising approach to treating triple negative breast cancer (TNBC). However, not all patients respond; we hypothesize that non-response in some patients may be due to insufficient drug penetration. As a first step to testing this hypothesis, we quantified and visualized veliparib and carboplatin penetration in mouse xenograft TNBCs and patient blood samples. Methods MDA-MB-231, HCC70 or MDA-MB-436 human TNBC cells were implanted in 41 beige SCID mice. Low dose (20 mg/kg) or high dose (60 mg/kg) veliparib was given three times daily for three days, with carboplatin (60 mg/kg) administered twice. In addition, blood samples were analyzed from 19 patients from a phase 1 study of carboplatin + PARPi talazoparib. Veliparib and carboplatin was quantified using liquid chromatography–mass spectrometry (LC-MS). Veliparib tissue penetration was visualized using matrix-assisted laser desorption/ionization mass spectrometric imaging (MALDI-MSI) and platinum adducts (covalent nuclear DNA-binding) were quantified using inductively coupled plasma–mass spectrometry (ICP-MS). Pharmacokinetic modeling and Pearson’s correlation were used to explore associations between concentrations in plasma, tumor cells and peripheral blood mononuclear cells (PBMCs). Results Veliparib penetration in xenograft tumors was highly heterogeneous between and within tumors. Only 35% (CI 95% 26–44%), 74% (40–97%) and 46% (9–37%) of veliparib observed in plasma penetrated into MDA-MB-231, HCC70 and MDA-MB-436 cell-based xenografts, respectively. Within tumors, penetration heterogeneity was larger with the 60 mg/kg compared to the 20 mg/kg dose (RSD 155% versus 255%, P = 0.001). These tumor concentrations were predicted similar to clinical dosing levels, but predicted tumor concentrations were below half maximal concentration values as threshold of response. Xenograft veliparib concentrations correlated positively with platinum adduct formation (R 2 = 0.657), but no PARPi–platinum interaction was observed in patients’ PBMCs. Platinum adduct formation was significantly higher in five gBRCA carriers (ratio of platinum in DNA in PBMCs/plasma 0.64% (IQR 0.60–1.16%) compared to nine non-carriers (ratio 0.29% (IQR 0.21–0.66%, P

Background Adipose fat transfer is increasingly used for contour corrections of the tumor bed after lumpectomy and breast reconstructions after mastectomy. The lipophilic nature of the fat tissue may render adipocytes an ideal vehicle with which to deliver a high boost of an antiestrogen to the tumor bed to serve as an adjunct systemic hormonal therapy. The authors therefore tested whether adipocytes could safely be loaded with an antiestrogen and allow for release at therapeutic concentrations to treat breast cancer. Methods Adipose tissue was collected from patients undergoing autologous fat grafting. The influence of adipose tissue on tumorigenesis was determined both in vitro and in vivo using breast cancer cell lines. Ex vivo, adipose tissue was assessed for its ability to depot fulvestrant and inhibit the growth of breast cancer cell lines. Results Adipose tissue harvested from patients did not promote breast cancer cell growth in vitro or in an in vivo mouse model. Adipose tissue was successfully loaded with fulvestrant and released at levels sufficient to inhibit estrogen receptor signaling and growth of breast cancer cells. Conclusions This work supports the hypothesis that adipose tissue used for autologous fat grafting can serve as a novel method for local drug delivery. As this technique is used to reconstruct a variety of postsurgical defects following cancer resection, this approach for local drug delivery may be an effective alternative in therapeutic settings beyond breast cancer.

Purpose This phase I trial evaluated epigenetic modulation of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor by using a histone deacetylase abexinostat in combination with pazopanib to enhance response and reverse resistance. Patients and Methods Pazopanib was administered once a day on days 1 to 28 and abexinostat was administered orally twice a day on days 1 to 5, 8 to 12, and 15 to 19 (schedule A) or on days 1 to 4, 8 to 11, and 15 to 18 (schedule B). Dose escalation (3 + 3 design) in all solid tumors was followed by dose expansion in renal cell carcinoma (RCC). Results Fifty-one patients with RCC (N = 22) were enrolled, including 30 (59%) with one or more lines of prior VEGF-targeting therapy. Five dose-limiting toxicities, including fatigue (n = 2), thrombocytopenia (n = 2), and elevated AST/ALT (n = 1), were observed with schedule A; one dose-limiting toxicity was observed (elevated AST/ALT) was observed with schedule B. Grade ≥ 3 related adverse events included fatigue (16%), thrombocytopenia (16%), and neutropenia (10%). The recommended phase II dose was established as abexinostat 45 mg/m2 twice a day administered per schedule B plus pazopanib 800 mg/d. Objective response rate was 21% overall and 27% in the RCC subset. Median duration of response was 9.1 months (1.2 to > 49 months). Eight patients (16%) had durable control of disease for > 12 months. Durable tumor regressions were observed in seven (70%) of 10 patients with pazopanib-refractory disease, including one patients with RCC with ongoing response > 3.5 years. Peripheral blood histone acetylation and HDAC2 gene expression were associated with durable response to treatment. Conclusion Abexinostat is well tolerated in combination with pazopanib, allowing prolonged exposure and promising durable responses in pazopanib- and other VEGF inhibitor-refractory tumors, which supports epigenetically mediated reversal of treatment resistance.

3022 Background: We previously reported the initial phase 1b study results of PAZ + ABX, a potent pan-HDAC inhibitor, demonstrating acceptable toxicity profile and encouraging anti-tumor activity (Aggarwal et al. JCO 2017). We report the long-term follow up of exceptional responders and additional correlative analyses associated with clinical outcomes. Methods: Key efficacy endpoints included objective response rate and duration of response. Peripheral blood histone acetylation, HDAC expression, and plasma VEGF levels were analyzed and associated with clinical outcomes. Results: 51 pts (RCC subset; N = 22) were enrolled between June 2012 and October 2015. 10 pts (20%) had experienced disease progression on prior PAZ; 59% had received any prior VEGF-targeting therapy. 9 evaluable pts (18%) (N = 6 RCC; 2 thyroid; 1 mesothelioma) achieved partial tumor response (PR), of which 6 had prior progression on VEGF-targeting therapy. 7/10 (70%) of pts with prior disease progression on PAZ monotherapy had reduction in tumor burden on study. The median duration of response was 9.1 months (range 1.2 to 70+), and clinical benefit rate (PR or stable disease > 6 months) was 33%. Five treatment-refractory pts achieved durable PRs lasting for > 2 years duration, and one previously PAZ-refractory patient with RCC remains on treatment with ongoing PR for > 6 years. Higher HDAC2 expression was associated with prolonged progression-free survival (median PFS 5.9 vs. 3.5 months, log-rank p = 0.02). Induction of histone acetylation on ABX lead-in treatment was associated with subsequent time to progression (p = 0.002). On-treatment plasma VEGF levels were inversely correlated with PBMC histone acetylation (p = 0.02). Conclusions: Markedly durable responses with PAZ + ABX are achievable, including in pts with PAZ- and VEGF-refractory RCC and other solid tumor malignancies. Host factors including HDAC expression and acetylation status may identify those most likely to benefit. A randomized phase 3 study is underway of PAZ + ABX as a first- or second-line therapy in pts with locally advanced or metastatic RCC (RENAVIV; NCT03592472). Clinical trial information: NCT01543763.

Background: Breast cancer remains one of the most serious and common diseases, second only to lung cancer as a leading cause of cancer death in women, accounting for 30% of new diagnoses. In particular, hormone-sensitive metastatic breast cancer and triple-negative breast cancer (TNBC) remains a therapeutic challenge. Despite aggressive therapeutic options, resistance develops in almost all patients and survival remains poor, prompting the need for novel approaches. This project focuses on the characterization of the molecular mechanisms underlying epigenetic modifiers and in particular Histone deacetylase inhibitors (HDACi) as priming modulators of immunotherapy, mainly focusing on the diversity between TNBC and hormone responsive breast cancer. HDACi represent a new class of anticancer agents that can affect multiple cancer pathways, including reverse hormone therapy resistance, resulting in prolonged antitumor responses in patients. In addition to their effects on tumor signaling, HDACi have immune modulatory functions, including modulation of regulatory T-cells, Foxp3 expression, changes in tumor-infiltrating lymphocyte composition and induction of PD-L1 expression. The PD-1/PD-L1 pathway is an immune checkpoint inhibitor pathway that under normal conditions down-regulates cytotoxic T-cell activity to maintain immune homeostasis. Cancer cells take advantage of this pathway to suppress immune control and inhibit the anti-tumor immune response by deactivating cytotoxic T-cells in the tumor microenvironment. Breast cancer is considered a less immunogenic cancer compared to melanoma and lung cancer. PD-L1 expression is mainly found in TNBC, HER2+, ER- and PR- tumors. Increased PD-L1 expression correlates with higher tumor infiltrating lymphocytes and those data together correlate with better response in breast cancer patients. PD-1/PD-L1 pathway represents one of the primary immunosuppressive drivers in multiple types of cancer. Thus, inhibiting PD-1/PD-L1 interactions may prevent T-cell suppression and reactivate immune-surveillance. Methods and Results: Evaluating PD-L1 basal expression in a different set of human and mouse breast cancer cell lines by Western blotting and real-time PCR, we found TNBC and HER2+ cells express the highest PD-L1 levels. Testing different epigenetic modifiers, we found that HDACi were able to up-regulate PD-L1 mRNA and protein expression in a time-dependent manner up to 72 hours in the TNBC MDA-MB231 cells. Co-culturing tumor cells with human peripheral blood mononuclear cell (PBMCs), we performed comprehensive flow cytometric immunophenotyping to define the role of epigenetic priming in promoting immune cell activation. We found that HDACi upregulate PD-L1 and HLA-DR expression on MDA-MB231 tumor cells independently from PBMCs presence. Opposite effects were observed with hormone responsive ER+ MCF-7 cells, where PD-L1 was not significantly increased and HLA-DR was down-regulated upon HDACi treatment. These effects were associated with reduced Foxp3 expression on CD4+ Tregs in vitro after HDACi treatment. Importantly, HDACi significantly enhanced the in vivo response to PD-1 and CTLA-4 blockade in the triple-negative 4T1 breast cancer mouse model. This was associated with increased tumor infiltrating T cells, increased survival, and tumor growth inhibition in vivo. Conclusion: Overall, this study suggests that the combination of HDACi with immune checkpoint inhibitors identify a novel therapeutic strategy and warrants further clinical evaluation for the treatment of TNBC. Citation Format: Manuela Terranova Barberio, Scott Thomas, Niwa Ali, Nela Pawlowska, Jeenah Park, Michael D. Rosenblum, Alfredo Budillon, Pamela N. Munster. HDAC inhibition modulates immune checkpoint pathway in triple-negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B10.

1044Background: Immune checkpoint inhibitors have revolutionized cancer therapy, yet have limited efficacy in estrogen receptor (ER)+ breast cancer. Implicated factors include scarcity of tumor inf...

This abstract was not presented at the symposium.

Purpose: Synthetic toxicity of PARP inhibitors (PARPi) and platinum salts may prohibit combination therapy in cells vulnerable to DNA damage and require alternate dosing schedule in germline BRCA (gBRCA) carriers. Experimental Design: In a phase 1 study we evaluated the safety, tolerability, pharmacokinetics (PK), and efficacy of talazoparib (PARPi) and carboplatin. Pharmacokinetic-modeling explored associations between DNA vulnerability and hematologic toxicity. Differential toxicity profiles between gBRCA carriers compared to non-BRCA carriers were assessed using a PK-toxicity model accounting for dose delivery and variability in talazoparib PK. A previously developed semi-mechanistic hematologic toxicity model was used to estimate the effect of talazoparib and carboplatin on platelets and white blood cells, accounting for dose delivery of carboplatin and talazoparib and variability in talazoparib PK. To assess synergy, we compared carboplatin adduct formation alone and when used with a PARPi measured by ICP-MS in patient blood samples and fresh frozen mouse xenograft tumor sections. Results: 24 patients (8M: 16F) with solid tumors were enrolled in 4 cohorts at 0.75mg and 1mg daily talazoparib and weekly carboplatin (AUC 1 and 1.5, Q2W or Q3W). Dose-limiting toxicities included grade 3 fatigue and grade 4 thrombocytopenia; the maximum tolerated dose was not reached. Grade 3/4 toxicities included fatigue (13%), neutropenia (63%), thrombocytopenia (29%), and anemia (38%). Post-cycle 2 dose delays/reductions were required in all patients. One complete and two partial responses occurred in gBRCA patients. Four patients showed stable disease beyond four months. PK-toxicity modeling suggests that after 3 cycles of carboplatin AUC 1.5 Q3W and talazoparib 1mg daily, neutrophil counts decreased by 78% (CI: 87 to 68%) from baseline in gBRCA carriers and 63% (CI: 72 to 55%) in noncarriers (p Citation Format: Mallika Sachdev Dhawan, Imke Heleen Bartelink, Rahul Aggarwal, Nela Pawlowska, Manuela Terranova-Barberio, Scott Thomas, Pamela Munster. Pharmacokinetic modeling of differential toxicity to predict alternate dosing schedules [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A090.

Background: Talazoparib is a novel PARP inhibitor (PARPi) in clinical development. Synergistic anti-tumor effects of PARPi and chemotherapy have been observed in preclinical models. This Phase 1 trial evaluates the tolerability, dose limiting toxicities (DLT) and efficacy of talazoparib in combination with carboplatin in patients with or without germ line DNA repair mutations. We hypothesize that talazoparib may overcome carboplatin resistance but induce greater toxicity in patients with DNA repair defects. Methods: Talazoparib and carboplatin pharmacokinetics (PK), safety and anti-tumor activity were evaluated in a 3+3 dose escalation design. Genetic testing, PK, pharmacodynamic effects (PD), biomarkers, and alternate dose modeling were evaluated to better understand the interaction of carboplatin and talazoparib. Results: 24 patients (median age 59y) were enrolled in 4 cohorts and treated with talazoparib 0.75 or 0.1 mg/day and carboplatin AUC 1 or 1.5 for 3/3 or 2/3 weeks. Tumor types included: breast (n = 11), prostate (n = 5), cholangiocarcinoma (n = 2), ovarian (n = 2), bladder (n = 1), adenoid cystic carcinoma (n = 1) and adenocarcinoma of unknown origin (n = 2). Germline mutations were noted in BRCA1 (n = 3), BRCA2 (n = 3), BRIP1 (n = 1), and MSH6 (n = 1) and germ line variants of uncertain significance in BRIP1 (n = 1) and BRCA2 (n = 1). Somatic mutations were found in BRCA2 (n = 1), BAP1 (n = 2) and PALB2 (n = 1). DLTs included fatigue and thrombocytopenia; other non-DLT grade 3/4 toxicities included fatigue (13%), neutropenia (33%), thrombocytopenia (33%), and anemia (58%). Post cycle 1 hematological toxicities required dose delays and reductions in almost all patients. One complete response occurred in a patient with germline BRCA1 (gBRCA1) breast cancer and a partial response (PR) in a gBRCA2 bladder cancer patient; 11 patients (pts) had stable disease (SD) for ?3 months. 5 pts had progressive disease (PD) and 6 pts are not yet evaluable. Of those with PD, 83% had prior platinum therapy, whereas in those with SD or disease response, 46% had prior platinum therapy. Effects of talazoparib/carboplatin on platelet (-11.4% vs. -1.1% P Conclusions: Mutation carriers in BRCA or other DNA repair genes responded better to this combination than non-carriers. Progression with prior platinum or PARPi did not exclude response or clinical benefit. Talazoparib and carboplatin showed significant hematologic toxicity in those with gBRCA or other germ line DNA repair mutations. Lower dosing frequencies of carboplatin when given with PARPi may be required in gBRCA mutation carriers. Citation Format: Mallika S. Dhawan, Rahul Aggarwal, Imke Bartelink, Jim Leng, Scott Thomas, Nela Pawlowska, Laurie Stevenson, Amy Jo Chien, Robin Kate Kelley, Pamela N. Munster. Carboplatin and talazoparib combination therapy results in differential efficacy and hematologic toxicity in BRCA-mutated patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT051.

TPS620Background: Immunotherapy with checkpoint inhibitors in estrogen receptor (ER) + breast cancer has been less effective than in other diseases. This in part is due to the scarcity of tumor inf...

2557Background: Synergistic anti-tumor effects of PARPi and chemotherapy have been observed in preclinical models. This Phase 1 trial evaluates the tolerability, dose limiting toxicities (DLT) and ...