Search

Ripretinib is a switch control KIT kinase inhibitor approved for treatment of adults with advanced gastrointestinal stromal tumors who received prior treatment with 3 or more kinase inhibitors, including imatinib. Ripretinib and its active metabolite (DP-5439) are cleared mainly via cytochrome P450 enzyme 3A4/5 (CYP3A4/5), and ripretinib solubility is pH-dependent, thus the drug-drug interaction potentials of ripretinib with itraconazole (strong CYP3A inhibitor), rifampin (strong CYP3A inducer), and pantoprazole (proton pump inhibitor) were each evaluated in open-label, fixed-sequence study designs. Overall, 20 participants received ripretinib 50 mg alone and with itraconazole 200 mg once daily, 24 participants received ripretinib 100 mg alone and with rifampin 600 mg once daily, and 25 participants received ripretinib 50 mg alone and with pantoprazole 40 mg once daily. Ripretinib exposure increased with concomitant itraconazole, with geometric least-squares (LS) mean ratios of ripretinib area under the concentration-time curve from 0 to ∞ (AUC

PDF file - 70KB, Supplementary Table 2. Grade 3/4 Adverse Events that Occurred in ≥2% of Patients.

PDF file - 490KB, Supplementary Figure 2. Effects of SAR245409 on Plasma Fasting Insulin and Fasting Glucose.

PDF file - 4775KB, Supplementary Figure 3. Reduction in Extracellular Signal-Regulated Kinase (ERK) Pathway Signaling by SAR245409 in Paired Tumor Biopsies.

PDF file - 1005KB, Supplementary Figure 1. Mean (+ or - SE) SAR245409 Plasma Concentration-Time Profiles on Days 1 and 27 of Cycle 1.

PDF file - 1779KB, Supplementary Figure 4. Effect of SAR245409 on Skin Lesions of a Ductal Breast Carcinoma Patient.

PDF file - 123KB

Purpose: This phase I, first-in-human study evaluated the safety, maximum-tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary efficacy of SAR245409, an inhibitor of pan-Class I phosphoinositide 3-kinase (PI3K) and mTOR, administered orally once or twice daily in patients with advanced solid tumors.Experimental Design: Eighty-three patients received SAR245409. Doses ranged from 15 to 120 mg twice daily, and 70 to 100 mg once daily. A 3+3 dose-escalation design was used to determine the MTD. Patients were evaluated for adverse events and response. Assessments included pharmacokinetic, pharmacodynamic impact of SAR245409 on PI3K pathway signaling in hair sheath cells, skin and tumor, and characterization of tumor molecular alterations.Results: The MTDs were 50 mg twice daily and 90 mg once daily. The most frequent treatment-related adverse events were nausea (36.1%), diarrhea (21.7%), vomiting (19.3%), and decreased appetite (16.9%). The most frequent treatment-related grade 3/4 adverse events were increases in alanine aminotransferase (6.0%) and aspartate aminotransferase (4.8%). SAR245409 had a relatively short plasma half-life (2.96–7.52 hours). At MTDs, once- and twice-daily regimens yielded similar mean steady-state plasma exposure. A reduction in PI3K and mTORC1/mTORC2 pathway signaling was observed in serial hair sheath cells, skin, and tumor samples. Best response was stable disease in 48% of evaluable patients; seven patients had minor tumor regression. Twelve patients with stable disease were treated for ≥16 weeks. No trend was observed correlating tumor molecular alteration with antitumor activity.Conclusion: SAR245409 had a manageable safety profile, demonstrated reduced PI3K and mTORC1/mTORC2 pathway signaling and was associated with clinically relevant stable disease. Clin Cancer Res; 20(9); 2445–56. ©2014 AACR.

PDF file - 49KB

PDF file - 77KB, Supplementary Table 1. Adverse Events that Occurred in ≥10% of Patients.

PDF file - 89KB, Supplementary Table 3. Reduction in Phosphoinositide 3-kinase and Mammalian Target of Rapamycin Complex 1 (mTORC1)/mTORC2 Pathway Signaling in Paired Tumor Biopsies.

PURPOSE Sunitinib, a multitargeted tyrosine kinase inhibitor (TKI), is approved for advanced gastrointestinal stromal tumor (GIST) after imatinib failure. Ripretinib is a switch-control TKI approved for advanced GIST after prior treatment with three or more TKIs, including imatinib. We compared efficacy and safety of ripretinib versus sunitinib in patients with advanced GIST who were previously treated with imatinib (INTRIGUE, ClinicalTrials.gov identifier: NCT03673501 ). PATIENTS AND METHODS Random assignment was 1:1 to once-daily ripretinib 150 mg or once-daily sunitinib 50 mg (4 weeks on/2 weeks off) and stratified by KIT/ platelet-derived growth factor α mutation and imatinib intolerance. The primary end point was progression-free survival (PFS) by independent radiologic review using modified Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included objective response rate by independent radiologic review, safety, and patient-reported outcome measures. RESULTS Overall, 453 patients were randomly assigned to ripretinib (intention-to-treat [ITT], n = 226; KIT exon 11 ITT, n = 163) or sunitinib (ITT, n = 227; KIT exon 11 ITT, n = 164). Median PFS for ripretinib and sunitinib ( KIT exon 11 ITT) was 8.3 and 7.0 months, respectively (hazard ratio, 0.88; 95% CI, 0.66 to 1.16; P = .36); median PFS (ITT) was 8.0 and 8.3 months, respectively (hazard ratio, 1.05; 95% CI, 0.82 to 1.33; nominal P = .72). Neither was statistically significant. Objective response rate was higher for ripretinib versus sunitinib in the KIT exon 11 ITT population (23.9% v 14.6%, nominal P = .03). Ripretinib was associated with a more favorable safety profile, fewer grade 3/4 treatment-emergent adverse events (41.3% v 65.6%, nominal P < .0001), and better scores on patient-reported outcome measures of tolerability. CONCLUSION Ripretinib was not superior to sunitinib in terms of PFS. However, meaningful clinical activity, fewer grade 3/4 treatment-emergent adverse events, and improved tolerability were observed with ripretinib.

Purpose: Most patients with gastrointestinal stromal tumor (GIST) have activating mutations in KIT/PDGFRA and are initially responsive to tyrosine kinase inhibitors (TKI). The acquisition of secondary mutations leads to refractory/relapsed disease. This study reports the results of an analysis from the phase III INVICTUS study (NCT03353753) characterizing the genomic heterogeneity of tumors from patients with advanced GIST and evaluating ripretinib efficacy across KIT/PDGFRA mutation subgroups. Patients and Methods: Tumor tissue and liquid biopsy samples that captured circulating tumor DNA were collected prior to study enrollment and sequenced using next-generation sequencing. Subgroups were determined by KIT/PDGFRA mutations and correlation of clinical outcomes and KIT/PDGFRA mutational status was assessed. Results: Overall, 129 patients enrolled (ripretinib 150 mg once daily, n = 85; placebo, n = 44). The most common primary mutation subgroup detected by combined tissue and liquid biopsies were in KIT exon 11 (ripretinib, 61.2%; placebo, 77.3%) and KIT exon 9 (ripretinib, 18.8%; placebo, 15.9%). Patients receiving ripretinib demonstrated progression-free survival (PFS) benefit versus placebo regardless of mutation status (HR 0.16) and in all assessed subgroups in Kaplan–Meier PFS analysis (exon 11, P < 0.0001; exon 9, P = 0.0023; exon 13, P < 0.0001; exon 17, P < 0.0001). Among patients with wild-type KIT/PDGFRA by tumor tissue, PFS ranged from 2 to 23 months for ripretinib versus 0.9 to 10.1 months for placebo. Conclusions: Ripretinib provided clinically meaningful activity across mutation subgroups in patients with advanced GIST, demonstrating that ripretinib inhibits a broad range of KIT/PDGFRA mutations in patients with advanced GIST who were previously treated with three or more TKIs.

Purpose: Ripretinib is a switch-control tyrosine kinase inhibitor that broadly inhibits KIT and platelet-derived growth factor receptor a kinase signalling. Ripretinib showed preliminary efficacy in patients with advanced gastrointestinal stromal tumour (GIST) in a phase I study across a range of doses. Results were confirmed in the phase III INVICTUS study, and ripretinib 150 mg once daily (QD) was subsequently approved as a >fourth-line therapy. Here, we report the phase I study results of intrapatient dose escalation (IPDE) in patients with GIST treated across second, third and later lines of therapy. Methods: Patients with advanced GIST who experienced disease progression (PD) at ripretinib 150 mg QD could dose escalate to 150 mg twice daily (BID). Progression-free survival (PFS) 1 was calculated from the date of the first dose of ripretinib 150 mg QD to PD (as per Response Evaluation Criteria in Solid Tumours 1.1); PFS2 was from the date of IPDE (150 mg BID) to PD or death. Treatment-emergent adverse events (TEAEs) were summarised by dosing periods and compared descriptively. Results: Of 142 patients with GIST receiving ripretinib 150 mg QD, 67 underwent IPDE. IPDE provided benefit across all lines of therapy; the median PFS2 was 5.6, 3.3 and 4.6 months for patients on second-, third-and >fourth-line therapy, respectively. A partial metabolic response after IPDE was demonstrated in 13 of 37 patients with available positron emission tomography scans. TEAEs reported at both doses were similar. Conclusion: Ripretinib IPDE after PD provided continued clinical benefit in advanced GIST across second, third and later lines of therapy with a similar safety profile to that observed with the QD regimen. (c) 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

397784 Background: Ripretinib, a switch-control tyrosine kinase inhibitor (TKI), is indicated for patients (pts) with gastrointestinal stromal tumor (GIST) who received prior treatment with ≥3 TKIs, including imatinib. Sunitinib is approved for advanced GIST after imatinib failure. Circulating tumor DNA (ctDNA) analysis may provide insight into the efficacy of these agents in second-line advanced GIST. Here, we present exploratory baseline ctDNA results from INTRIGUE. Methods: INTRIGUE is an open-label, phase 3 study that enrolled adult pts with advanced GIST who progressed on or had intolerance to imatinib (NCT03673501). Randomization was 1:1 to ripretinib 150 mg once daily (QD) or sunitinib 50 mg QD (4 wks on/2 wks off). Baseline peripheral whole blood was analyzed by Guardant360, a 74-gene ctDNA next-generation sequencing (NGS)-based assay. Only KIT mutations are reported here. Results: Of 453 pts in the overall intent-to-treat (ITT) population, 362 (80%) samples were analyzed. ctDNA was detected in 280/362 (77%), with KIT mutations detected in 213/280 (76%). Common resistance mutations were in the KIT activation loop (AL; exons 17/18; 89/213, 42%) and ATP-binding pocket (ATP-BP; exons 13/14; 81/213, 38%). Efficacy in pts with detectable ctDNA in the KIT exon 11 and overall ITT populations was consistent with the primary analysis based on tumor data used for randomization. Pts with KIT exon 11 + 17/18 (−9/13/14) mutations had superior progression-free survival (PFS), objective response rate (ORR), and overall survival (OS) with ripretinib vs sunitinib, whereas pts with exon 11 + 13/14 (−9/17/18) mutations had better PFS, ORR, and OS with sunitinib vs ripretinib (Table). Subgroup safety profiles were consistent with the primary analysis. Conclusions: While KIT ATP-BP mutations predicted clinical benefit from sunitinib vs ripretinib, pts harboring resistance mutations in the KIT AL derived meaningful clinical benefit from ripretinib but not sunitinib. This study demonstrates the value of ctDNA NGS-based sequencing of the complex landscape of KIT mutations to predict the clinical benefit of ripretinib or sunitinib as second-line therapy in pts with advanced GIST. Clinical trial information: NCT03673501 . [Table: see text]

11541 Background: Ripretinib (R) is a switch-control tyrosine kinase inhibitor (TKI) indicated for the treatment of patients (pts) with advanced gastrointestinal stromal tumor (GIST) after prior treatment with ≥3 TKIs. In the INTRIGUE study (NCT03673501) there was no significant difference in median PFS (primary endpoint) between R and sunitinib (S). We present exploratory analyses of tolerability data and selected pt reported outcomes (PROs). Methods: Pts were randomized 1:1 to R 150 mg QD or S 50 mg QD 4 weeks on/2 weeks off.Dose modification was allowed for toxicity management. The event of interest was severe or life-threatening (grade ≥3) treatment-related adverse event prior to progression (sTRAE). Days with at least one sTRAE were summed for all treated pts and for pts with ≥1 sTRAE event. PROs were assessed using questions from EORTC QLQ-C30 and Dermatology Life Quality Index (DLQI) at cycle 1 (C1) day 1 (D1), D15, and D29; D1 and D29 of all other cycles; as well as at end of treatment. Differences in PRO scores between baseline and later assessments were calculated across visits. Long-term data will be presented. Results: Pts receiving R (n = 223) versus (vs) S (n = 221) experienced fewer sTRAEs (24% vs 51%, respectively). For all treated pts, the mean time with sTRAEs was 11 days for R and 42 days for S (ratio 0.27, P

Macrophages can be co-opted to contribute to neoplastic, neurologic, and inflammatory diseases. Colony-stimulating factor 1 receptor (CSF1R)-dependent macrophages and other inflammatory cells can suppress the adaptive immune system in cancer and contribute to angiogenesis, tumor growth, and metastasis. CSF1R-expressing osteoclasts mediate bone degradation in osteolytic cancers and cancers that metastasize to bone. In the rare disease tenosynovial giant cell tumor (TGCT), aberrant CSF1 expression and production driven by a gene translocation leads to the recruitment and growth of tumors formed by CSF1R-dependent inflammatory cells. Small molecules and antibodies targeting the CSF1/CSF1R axis have shown promise in the treatment of TGCT and cancer, with pexidartinib recently receiving FDA approval for treatment of TGCT. Many small-molecule kinase inhibitors of CSF1R also inhibit the closely related kinases KIT, PDGFRA, PDGFRB, and FLT3, thus CSF1R suppression may be limited by off-target activity and associated adverse events. Vimseltinib (DCC-3014) is an oral, switch control tyrosine kinase inhibitor specifically designed to selectively and potently inhibit CSF1R by exploiting unique features of the switch control region that regulates kinase conformational activation. In preclinical studies, vimseltinib durably suppressed CSF1R activity in vitro and in vivo, depleted macrophages and other CSF1R-dependent cells, and resulted in inhibition of tumor growth and bone degradation in mouse cancer models. Translationally, in a phase I clinical study, vimseltinib treatment led to modulation of biomarkers of CSF1R inhibition and reduction in tumor burden in TGCT patients.

TPS11590 Background: Tenosynovial giant cell tumor (TGCT) is a rare, locally aggressive neoplasm that occurs in the synovium of joints, bursae, or tendon sheaths. TGCT is caused by upregulation of the colony-stimulating factor 1 (CSF1) gene, resulting in aberrant CSF1 expression and the recruitment of CSF1 receptor (R)-dependent inflammatory cells. Resection is the primary treatment, but nonsurgical treatment options are necessary for patients with symptomatic TGCT not amenable to surgical resection. Vimseltinib is an oral switch control TKI specifically designed to selectively and potently inhibit CSF1R. In a Phase 1/2 study in patients with TGCT, vimseltinib showed encouraging antitumor activity with an overall objective response rate (ORR) of 42% in the cohort receiving 30 mg twice weekly (recommended phase 2 dose; Gelderblom et al, ESMO 2021 Poster). Vimseltinib was also well tolerated, and the majority of the common (≥15%) treatment-emergent adverse events (TEAEs) were Grades 1–2. Among these common TEAEs, the only Grade 3–4 event in the Phase 2, twice-weekly, 30-mg cohort was increased blood creatine phosphokinase (CPK); however, this elevated CPK was not associated with any symptoms (Gelderblom et al, ESMO 2021 Poster). Phase 1/2 efficacy and safety data support further development of vimseltinib; here, we describe the ongoing Phase 3 study for patients with TGCT not amenable to surgical resection. Methods: MOTION (NCT05059262) is a Phase 3, randomized, placebo-controlled, double-blind study that aims to evaluate the efficacy and safety of vimseltinib for the treatment of TGCT not amenable to surgical resection. Participants must be at least 18 years of age and have histologically confirmed and symptomatic TGCT for which surgical resection will potentially cause worsening functional limitation or severe morbidity. Prior CSF1R therapy is not permitted (previous imatinib and nilotinib is allowed). In Part 1 of the study, eligible participants will be randomized 2:1 to receive either vimseltinib 30 mg twice a week or matched placebo for 24 weeks. The primary outcome measure is ORR assessed by central read using Response Evaluation Criteria in Solid Tumors version 1.1 at 25 weeks. Secondary outcome measures include ORR per tumor volume score, range of motion, and patient-reported outcomes. Participants assigned to placebo in Part 1 will have the option to receive vimseltinib in Part 2, a long-term treatment phase in which participants will receive open-label vimseltinib. This international study plans to randomize 120 participants and is currently enrolling. Clinical trial information: NCT05059262.

e16031 Background: Ripretinib is a tyrosine kinase inhibitor indicated for the treatment of patients with advanced gastrointestinal stromal tumor who have received prior treatment with ≥3 kinase inhibitors, including imatinib. Ripretinib and its active metabolite (DP-5439) are CYP3A substrates and coadministration with itraconazole (CYP3A inhibitor) increased exposure to each analyte by ̃100%. Therefore, we studied ripretinib in subjects with varying degrees of hepatic impairment (HI). Methods: Subjects with mild, moderate, and severe HI based on Child-Pugh, and matched healthy subjects received a single oral dose of ripretinib (50 mg, fasting) with 8 days of PK sampling. Concentrations of ripretinib and DP-5439 in plasma were measured by a liquid chromatography–tandem mass spectrometry (LC-MS/MS) assay. PK parameters were calculated using Phoenix WinNonlin, and the geometric least squares mean ratios and corresponding 90% confidence intervals of Cmax, AUC0-t, and AUC0-∞ (total and unbound) were calculated. Unbound concentrations were assessed at Tmax and 24 hours postdose. Results: Eight subjects with mild HI, 8 with moderate HI, 4 with severe HI, and 13 healthy matches were enrolled. As shown in the table, total ripretinib and DP-5439 PK was comparable for mild HI vs. healthy matches. For moderate HI, total ripretinib AUC was ̃100% higher (Cmax was comparable), whereas DP-5439 AUC was marginally higher (Cmax was 32% lower). For severe HI, total ripretinib AUC0-t was ̃160% higher and Cmax was ̃24% lower, whereas DP-5439 AUCs were ̃50% lower and Cmax was 78% lower. Unbound fraction was < 0.6% for ripretinib and 0.2-1.4% for DP-5439, with no clear trend with HI severity. The safety profile in HI subjects was similar to healthy matches; common adverse events (in ≥2 subjects) included increased lipase or amylase, diarrhea, and headache. Conclusions: Consistent with current labeling, mild HI had no impact on total PK. In this study, moderate and severe HI increased ripretinib AUC ̃100% and 163%, respectively. PK exposure to DP-5439 and combined ripretinib + DP-5439 was impacted to a lesser extent. Dose recommendations in moderate and severe HI are currently under development.[Table: see text]

PURPOSE In advanced gastrointestinal stromal tumor (GIST), there is an unmet need for therapies that target both primary and secondary mutations of pathogenic KIT/PDGFRA oncoproteins. Ripretinib is a novel switch-control kinase inhibitor designed to inhibit a wide range of KIT and PDGFRA mutations. PATIENTS AND METHODS This first-in-human, to our knowledge, phase I study of ripretinib (ClinicalTrials.gov identifier: NCT02571036) included a dose-escalation phase and subsequent expansion phase at the recommended phase II dose (RP2D). Eligible patients included those with advanced GIST, intolerant to or experienced progression on ≥ 1 line of systemic therapy, and other advanced malignancies. Safety, dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD), and preliminary antitumor activity were evaluated. RESULTS At data cutoff (August 31, 2019), 258 patients (n = 184 GIST) were enrolled, with 68 patients in the dose-escalation phase. Three DLTs were reported: grade 3 lipase increase (n = 2; 100 mg and 200 mg twice a day) and grade 4 increased creatine phosphokinase (n = 1; 150 mg once daily). MTD was not reached (maximum dose evaluated, 200 mg twice a day); 150 mg once daily was established as the RP2D. The most frequent (> 30%) treatment-emergent adverse events in patients with GIST receiving ripretinib 150 mg once daily (n = 142) were alopecia (n = 88 [62.0%]), fatigue (n = 78 [54.9%]), myalgia (n = 69 [48.6%]), nausea (n = 65 [45.8%]), palmar-plantar erythrodysesthesia (n = 62 [43.7%]), constipation (n = 56 [39.4%]), decreased appetite (n = 48 [33.8%]), and diarrhea (n = 47 [33.1%]). Objective response rate (confirmed) of 11.3% (n = 16/142) ranging from 7.2% (n = 6/83; fourth line or greater) to 19.4% (n = 6/31; second line) and median progression-free survival ranging from 5.5 months (fourth line or greater) to 10.7 months (second line), on the basis of investigator assessment, were observed. CONCLUSION Ripretinib is a well-tolerated, novel inhibitor of KIT and PDGFRA mutant kinases with promising activity in patients with refractory advanced GIST.

Purpose To characterize folate receptor alpha (FRα) expression in archival and fresh biopsy tumor samples from relapsed ovarian cancer patients. Methods Patients with ovarian tumors amenable to biopsy were eligible to enroll. Eligibility included a minimum requirement of FRα positivity in archival tumor samples (≥25% of cells with ≥2+ staining intensity). Patients received mirvetuximab soravtansine at 6mg/kg once every 3weeks. Core needle biopsies were collected before and after treatment and FRα levels assessed by immunohistochemistry. Descriptive statistics were used to summarize the association between receptor expression and response. Results Twenty-seven heavily pre-treated patients were enrolled. Six individuals (22%) did not have evaluable pre-treatment biopsies due to insufficient tumor cells. The concordance of FRα expression in archival and biopsy tissues was 71%, and no major shifts in receptor expression were seen in matched pre- and post-treatment biopsy samples. Adverse events were generally mild (≤grade 2) with keratopathy (48%), fatigue (44%), diarrhea, and blurred vision (each 37%) being the most common treatment-related toxicities. The confirmed objective response rate (ORR) was 22%, including two complete responses and four partial responses. Superior efficacy measures were observed in the subset of patients with the highest FRα levels (ORR, 31%; progression-free survival, 5.4months). Conclusion Concordance of FRα expression in biopsy versus archival tumor samples suggests that archival tissue can reliably identify patients with receptor-positive tumors and is appropriate for patient selection in mirvetuximab soravtansine clinical trials. Regardless of the tissue source analyzed, higher FRα expression was associated with greater antitumor activity.

Ripretinib (DCC-2618) is a novel, type II tyrosine switch control inhibitor designed to broadly inhibit activating and drug-resistant mutations in KIT and PDGFRA. Ripretinib has emerged as a promising investigational agent for the treatment of gastrointestinal stromal tumor owing to targeted inhibition of secondary resistance mutations that may develop following treatment with prior line(s) of tyrosine kinase inhibitors. Here we describe the rationale and design of intrigue (NCT03673501), a global, randomized (1:1), open-label, Phase III study comparing the safety and efficacy of ripretinib versus sunitinib in patients with advanced gastrointestinal stromal tumor following imatinib. The primary end point is progression-free survival and key secondary objectives include objective response rate and overall survival. Clinical Trial Registration: NCT03673501. ispartof: FUTURE ONCOLOGY vol:16 issue:1 pages:4251-4264 ispartof: location:England status: published

11539 Background: Ripretinib is a novel switch-control TKI that broadly inhibits KIT and PDGFRA kinase signaling. In INVICTUS (NCT03353753), a randomized, double-blind, placebo (PBO)-controlled trial of ripretinib in ≥4th-line advanced GIST, ripretinib reduced the risk of disease progression or death by 85% vs PBO with a favorable overall safety profile. Common ( > 20%) adverse events (AEs) included, but were not limited to, alopecia and PPES. Exploratory analyses evaluated the impact of alopecia and PPES on quality of life (QoL). Methods: Patients (pts) with advanced GIST previously treated with at least imatinib, sunitinib, and regorafenib were randomized (2:1) to ripretinib 150 mg QD or PBO. AEs were graded using CTCAE v4 and PROs collected using EQ-5D-5L (EQ5D) and EORTC QLQ-C30 (C30). Repeated measures (RM) models assessed the impact of alopecia and PPES on 5 PROs (EQ5D visual analogue scale; and C30 physical functioning, role functioning, and the overall health and overall QoL questions) within the ripretinib arm. Fixed effects were sex, alopecia/PPES, and ECOG scores at baseline. Results: 128/129 randomized pts received treatment (85 ripretinib 150 mg QD; 43 PBO). Alopecia, regardless of causality, occurred in 44 (51.8%) on ripretinib (34 [40.0%] grade 1; 10 [11.8%] grade 2) and 2 (4.7%) on PBO (both grade 1). PPES occurred in 18 (21.2%) on ripretinib (11 [12.9%] grade 1; 7 [8.2%] grade 2); none on PBO. The median times in days to first occurrence and worst severity grade with ripretinib were 57.0 and 62.5 for alopecia; 56.5 and 57.0 for PPES. The RM models showed a slight trend towards improvement in PRO score over time for pts with alopecia; the only association reaching a P-value of < 0.05 was between alopecia and increased overall QoL. None of the associations between PPES and PRO scores reach P < 0.05. All PRO p-values are nominal, and no statistical significance is being claimed. Conclusions: Ripretinib had a favorable overall safety and tolerability profile. When stratified by alopecia and PPES, patient-reported assessments of function, overall health, and overall QoL were maintained over time. For both alopecia and PPES, onset and maximum severity occurred almost simultaneously, indicating that these events generally did not progressively worsen. These results suggest that alopecia and PPES are manageable and do not have a negative effect on function, overall health, and QoL. Clinical trial information: NCT03353753 .

Background Resistance to approved inhibitors of KIT proto-oncogene, receptor tyrosine kinase (KIT), and platelet-derived growth factor receptor alpha (PDGFRA) is a clinical challenge for patients with advanced gastrointestinal stromal tumours. We compared the efficacy and safety of ripretinib, a switch-control tyrosine kinase inhibitor active against a broad spectrum of KIT and PDGFRA mutations, with placebo in patients with previously treated, advanced gastrointestinal stromal tumours.Methods In this double-blind, randomised, placebo-controlled, phase 3 study, we enrolled adult patients in 29 specialised hospitals in 12 countries. We included patients aged 18 years or older who had advanced gastrointestinal stromal tumours with progression on at least imatinib, sunitinib, and regorafenib or documented intolerance to any of these treatments despite dose modifications, and who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Eligible patients were randomly assigned (2:1) to receive either oral ripretinib 150 mg once daily (ripretenib group) or placebo once daily (placebo group). Randomisation was done via an interactive response system using randomly permuted block sizes of six and stratified according to number of previous therapies and ECOG performance status. Patients, investigators, research staff, and the sponsor study team were masked to a patient's treatment allocation until the blinded independent central review (BICR) showed progressive disease for the patient. The primary endpoint was progression-free survival, assessed by BICR. The primary analysis was done in the intention-to-treat population and safety was assessed in patients who received at least one dose of study drug. Patients randomly assigned to placebo were permitted to cross over to ripretinib 150 mg at the time of disease progression. The INVICTUS study is registered with ClinicalTrials.gov , number NCT03353753, and with WHO International Clinical Trials Registry Platform, number EUCTR2017-002446-76-ES; follow-up is ongoing.Findings Between Feb 27, 2018, and Nov 16, 2018, 129 of 154 assessed patients were randomly assigned to receive either ripretinib (n=85) or placebo (n=44). At data cutoff (May 31, 2019), at a median follow-up of 6.3 months (IQR 3. 2-8. 2) in the ripretinib group and 1.6 months (1.1-2.7) in the placebo group, 51 patients in the ripretinib group and 37 in the placebo group had had progression-free survival events. In the double-blind period, median progression-free survival was 6.3 months (95% CI 4.6-6.9) with ripretinib compared with 1.0 months (0.9-1.7) with placebo (hazard ratio 0.15, 95% CI 0.09-0.25; p2%) grade 3 or 4 treatment-related treatment-emergent adverse events in the ripretinib group (n=85) included lipase increase (four [5%]), hypertension (three [4%]), fatigue (two [2%]), and hypophosphataemia (two [2%]); in the placebo group (n=43), the most common (>2%) grade 3 or 4 treatment-related treatment-emergent adverse events were anaemia (three [7%]), fatigue (one [2%]), diarrhoea (one [2%]), decreased appetite (one [2%]), dehydration (one [2%]), hyperkalaemia (one [2%]), acute kidney injury (one [2%]), and pulmonary oedema (one [2%]). Treatment-related serious adverse events were reported in eight (9%) of 85 patients who received ripretinib and three (7%) of 43 patients who received placebo. Treatment-related deaths occurred in one patient in the placebo group (septic shock and pulmonary oedema) and one patient in the ripretinib group (cause of death unknown; the patient died during sleep).Interpretation Ripretinib significantly improved median progression-free survival compared with placebo and had an acceptable safety profile in patients with advanced gastrointestinal stromal tumours who were resistant to approved treatments. Copyright (C) 2020 Elsevier Ltd. All rights reserved.

Ripretinib is a tyrosine kinase inhibitor (TKI) indicated for the treatment of adult patients with advanced gastrointestinal stromal tumor (GIST) who have received prior treatment with 3 or more kinase inhibitors, including imatinib. In a phase 1 study (NCT02571036), the maximum tolerated dose was not reached at doses up to 200 mg twice daily (BID). Ripretinib 150 mg BID intrapatient dose escalation regimen was offered to patients in the phase 1 and 3 trials (INVICTUS, NCT03353753) after radiologic progression at 150 mg once daily (QD). The BID dose was well tolerated with a similar safety profile to the 150 mg QD (approved dose regimen). In this analysis, the population pharmacokinetics (popPK) of ripretinib and DP-5439, a metabolite TKI with in vitro activity and exposure similar to ripretinib, were characterized and potential covariates influencing exposure were evaluated. The popPK models were developed for ripretinib and DP-5439 using 5284 and 5160 quantifiable concentrations, respectively, from 350 patients pooled from the phase 1 and INVICTUS phase 3 studies. Models were estimated using first-order conditional estimation with interaction method in NONMEM® (version 7.3; ICON, Hanover, MD, USA) and evaluated based on standard goodness-of-fit metrics. A covariate analysis was conducted to assess the sources of variability in ripretinib pharmacokinetics (PK) using a full model approach with backward elimination (significance level = 0.005). Tested covariates included age, body weight, sex, race, tumor type, prior gastrectomy, and mild hepatic impairment and mild to moderate renal impairment. Ripretinib oral PK was well described by a 2-compartment model with zero-order drug release at the absorption site followed by first-order absorption with a modest, linear dose-dependent decrease in relative bioavailability and linear elimination. A high-fat meal was predicted to increase the ripretinib AUC by 36% at 150 mg QD relative to the fasted state. The only covariate effect retained in the final popPK model for ripretinib was 29% lower apparent clearance in females compared with males, resulting in a 40% higher AUC in females. No other covariates were identified for ripretinib. The resulting effect on DP-5439 was similar. PK exposure in patients with mild hepatic impairment or mild to moderate renal impairment was similar to that in patients with normal organ function. There were no clinically meaningful differences in the PK of ripretinib based on age, race, body weight, or tumor type. Based on the safety profile of ripretinib observed in patients with advanced GIST and PK variability, the effects of sex, fasted state, and prior gastrectomy on ripretinib PK were not considered clinically significant. Therefore, ripretinib can be taken with or without food by all patients and no dose adjustment is recommended for patients with mild hepatic impairment or patients with mild to moderate renal impairment. Citation Format: Suzanne George, Filip Janku, Ping Chi, Margaret von Mehren, Neeta Somaiah, Hans Gelderblom, Robin L. Jones, Martine Allard, Adekemi Taylor, Xiaoyan Li, Julie Meade, Vienna Reichert, Rodrigo Ruiz-Soto, Jing Wang, Michael C. Heinrich. Population pharmacokinetics of ripretinib in patients with advanced malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT123.

Ripretinib is a tyrosine kinase inhibitor indicated for the treatment of adult patients with advanced gastrointestinal stromal tumor who have received prior treatment with 3 or more kinase inhibitors, including imatinib. In a phase 1 study in patients with advanced malignancies, the maximum tolerated dose was not reached at doses up to 200 mg twice daily (BID). Dose escalation to ripretinib 150 mg BID was offered in the phase 1 and phase 3 clinical studies after radiologic disease progression at 150 mg once daily (QD) and was well tolerated with a similar safety profile as seen with 150 mg QD (approved dose regimen). Ripretinib solubility is pH dependent and ripretinib and its active metabolite (DP-5439) are cleared via CYP3A4/5; thus, drug-drug interactions (DDIs) with acid-reducing agents and strong CYP3A inhibitors/inducers were assessed. Here, we report the effects of pantoprazole (proton pump inhibitor), itraconazole (strong CYP3A inhibitor) and rifampin (strong CYP3A inducer) on the pharmacokinetics (PK) of ripretinib and DP-5439. Ripretinib PK is generally dose proportional within 50-150 mg. For each interaction, single oral doses of ripretinib (either 50 mg for pantoprazole and itraconazole or 100 mg for rifampin) were given before and concurrently with multiple doses of each perpetrator agent to healthy volunteers: pantoprazole 40 mg QD x 7 days (n = 25), itraconazole 200 mg QD x 10 days (n = 20), and rifampin 600 mg QD x 14 days (n = 24). Serial blood samples were collected over 4-7 days before and after each perpetrator drug; plasma concentrations of ripretinib and DP-5439 were determined by validated LC-MS/MS. The geometric least-squares mean (GLSM) ratios of PK parameters (i.e., AUC0-∞ and Cmax) and corresponding 90% confidence intervals (CIs) were calculated. No DDI was observed between ripretinib and pantoprazole. The ratios of GLSM and 90% CIs for AUC0-∞ and Cmax were within the bioequivalence 80%−125% range for ripretinib with pantoprazole vs ripretinib alone. Concomitant itraconazole increased exposure to ripretinib and DP-5439; GLSM ratios for ripretinib AUC0-∞ and Cmax were 199% and 136%, respectively, and similar ratios were noted for DP-5439. Exposure to ripretinib and DP-5439 based on AUC0-∞ decreased with rifampin coadministration. GLSM ratios for ripretinib AUC0-∞ and Cmax were 39% and 82%, respectively, for ripretinib with rifampin vs ripretinib alone, and were 43% and 137% for DP-5439. No dose adjustments are required when ripretinib is coadministered with either gastric acid reducers or strong CYP3A inhibitors, based on the magnitude of DDI PK effects in healthy volunteers, and the safety profile of ripretinib observed in patients and healthy volunteers. However, as decreased exposure may reduce the antitumor activity of ripretinib, concomitant use of strong CYP3A inducers with ripretinib should be avoided. Citation Format: Xiaoyan Li, Mark J. Shelton, Julie Meade, Cherie Taglienti, Constance Barysauskas, Rodrigo Ruiz-Soto, Jing Wang. Effect of gastric acid reduction and strong CYP3A induction/inhibition on the pharmacokinetics of ripretinib, a switch control tyrosine kinase inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT132.

11536 Background: Ripretinib is a switch-control tyrosine kinase inhibitor that broadly inhibits KIT and PDGFRA kinase signaling. In the INVICTUS study (NCT03353753), patients with advanced GIST (≥4th-line) receiving ripretinib had a median progression-free survival (mPFS) of 6.3 months vs 1.0 month for patients receiving placebo (HR = 0.15, p

5576 Background: Rebastinib is a first-in-class investigational, orally administered, potent and selective switch-control kinase inhibitor of tunica interna endothelial cell kinase (TIE2). This is a 2-part open-label, multicenter Phase 1b/2 study of rebastinib in combination with paclitaxel. Here we provide updated results (ASCO 2020) from the fully enrolled endometrial cancer (EC) cohort of the study. Methods: Part 2 of the study has five disease-specific cohorts (EC, platinum-resistant ovarian cancer, gynecological carcinosarcoma, TNBC and inflammatory breast cancer). Patients were treated at the RP2D and evaluated for efficacy (RECIST v1.1) and safety (CTCAE v5.0). Results: As of Jan 8, 2021, 38 EC patients were enrolled (median age of 66 years); 42% were of grade 2/3 endometroid histological subtype. All patients received at least 1 prior line of paclitaxel in combination with carboplatin and 79% of patients received ≥3 prior anti-cancer regimens. Sixteen of 38 patients were initially treated with a starting dose of rebastinib 100 mg BID, 11 of which dose reduced to 50 mg BID, and 22 patients were treated with a starting dose of rebastinib 50 mg BID, in combination with paclitaxel 80 mg/m2 IV weekly (days 1, 8, 15 of 28-day cycle). In 33 evaluable patients with median follow-up of 5.9 months, the ORR was 33% and clinical benefit rate at 8 and 16 weeks was 70% and 55%, respectively, including 11 PRs (8 confirmed) and 12 SDs. Treatment-emergent adverse events ( > 20% of patients; mostly ≤ grade 2) included fatigue (n = 18), constipation, peripheral edema (each at n = 16), peripheral sensory neuropathy, nausea (each at n = 15), dyspnea (n = 13), alopecia, hypokalemia (each at n = 11), diarrhea, hypomagnesemia (each at n = 10), dry mouth, dysgeusia (each at n = 9), arthralgia, hypertension, dehydration, GERD and muscular weakness (each at n = 8). Serious adverse events (SAE) at least possibly related to rebastinib included muscular weakness (n = 2 at 100 mg BID, n = 1 at 50 mg BID), nausea (n = 2), acute myocardial infarction, atrial flutter, dehydration, non-infective encephalitis, peritonsillitis, and stress cardiomyopathy (each at n = 1) and were resolved after dose interruption. Conclusions: The updated results of rebastinib at 50 mg BID in combination with paclitaxel showed encouraging preliminary anti-tumor activity and an acceptable safety profile in heavily pretreated EC patients, and supports further development in patients with EC (NCT03601897). Clinical trial information: NCT03601897.

6085 Background: Rebastinib is a switch control inhibitor targeting tunica interna endothelial cell kinase (TIE2). TIE2 is primarily expressed in endothelial cells playing a role in angiogenesis. TIE2 is also expressed in a subset of macrophages with pro-metastatic and immunosuppressive properties and linked to chemo-resistance. This study is a 2-part open-label, phase Ib/II, multicenter study of rebastinib orally administered, in combination with paclitaxel. In Part 1, we observed encouraging antitumor activity of rebastinib with 5 PRs in 24 patients (pts) at 50 mg BID and 3 PRs in 19 pts at 100 mg BID from a heavily pretreated heterogeneous patient population. Here we summarize preliminary results from the endometrial cancer (EC) cohort of Part 2. Methods: Part 2 of this study has four disease-specific cohorts (TNBC, inflammatory breast cancer, ovarian cancer and EC). Pts were evaluated for safety (CTCAE v5.0) and efficacy (RECIST v1.1). According to the Simon 2-stage design of this study, for each cohort, 15 additional pts will be enrolled if more than 4 PRs are observed. Results: As of Jan 21, 2020, 19 EC pts were enrolled with a median age of 66 years. All pts received at least one prior line of paclitaxel and 12 (63%) pts received >3 prior anti-cancer therapies. Sixteen pts were treated with rebastinib starting dose 100 mg BID (reduced to 50 mg BID due to a higher frequency of muscular weakness) and 3 pts with 50 mg BID, in combination with 80 mg/m2 weekly paclitaxel with a median duration of treatment 85 days (6, 225). In 15 evaluable pts, there were 5 PRs (4 confirmed) and 6 SD8 weeks for an ORR of 33% and clinical benefit rate of 73%. Treatment-emergent AEs (>20%) were mostly ≤ grade 2: constipation, fatigue (each n=9); alopecia, peripheral edema (each n=8); dysgeusia, peripheral sensory neuropathy, arthralgia (each n=6); diarrhea, hypomagnesaemia, vomiting, dry mouth (each n=5); anemia, decreased appetite, dyspnea, nausea, and muscular weakness (each n=4). Serious AEs possibly related or related to rebastinib included muscular weakness (n=2, at 100 mg BID), head discomfort (n=1) and increase troponin (n=1) which resolved after dose interruption. Conclusions: Preliminary activity of rebastinib in combination with paclitaxel was encouraging in heavily pretreated EC pts, all of whom received prior paclitaxel. The safety profile of rebastinib at 50 mg BID was generally well tolerated. The EC cohort is enrolling at 50 mg BID in stage 2 of the study. Clinical trial information: NCT03601897.

11535 Background: Ripretinib is a novel switch-control tyrosine kinase inhibitor (TKI) that broadly inhibits KIT and PDGFRA kinase signaling through a dual mechanism of action. In INVICTUS (NCT03353753), a randomized, double-blind, placebo-controlled trial of ripretinib in ≥4th-line advanced GIST, ripretinib reduced the risk of disease progression or death by 85% vs placebo and had a favorable overall safety profile in patients previously treated with ≥3 prior TKIs. Methods: As part of the INVICTUS trial, patient reported outcome (PRO) measures were collected using EQ-5D-5L (EQ5D) and EORTC QLQ-C30 (C30). In prespecified and additional analyses, ANCOVA models were built to compare changes from baseline to cycle 2 day 1 (C2D1) for PRO measures within the ripretinib and placebo arms and determine the difference between treatment arms. PRO measures included the EQ5D visual analogue scale (VAS) and the C30 physical functioning (PF) and role functioning (RF) scales (all scores range from 0–100; higher scores are better). The C30 overall health and overall QoL questions were also assessed (scores range from 1–7; higher scores are better). Fixed effects included treatment arm, number of previous anticancer treatments (3 vs ≥4), and ECOG score at baseline (0 vs 1/2). Results: Overall, 129 patients were randomized and 128 received treatment (85 to ripretinib 150 mg QD; 43 to placebo). All PRO p-values are nominal, and no statistical significance is being claimed. VAS scores improved an average 3.7 points from baseline to C2D1 with ripretinib vs an average decline of 8.9 with placebo (P = 0.004; improvement or no change, 67% vs 41% of patients, respectively). Similarly, the average PF score improved 1.6 points with ripretinib and decreased 8.9 with placebo (P = 0.004; improvement or no change, 68% vs 44%). RF scores also improved an average of 3.5 points with ripretinib vs a decrease of 17.1 with placebo (P = 0.001; improvement or no change, 77% vs 50%). For the overall health and overall QoL questions, scores increased with ripretinib an average of 0.20 and 0.28, respectively, and decreased 0.78 and 0.76 with placebo (both P = 0.001; improvement or no change, 74% vs 47% and 79% vs 59%, respectively). Conclusions: Based on the 5 PRO measures assessed, when compared with placebo and best supportive care, ripretinib provided patient-benefit in advanced GIST with PRO measures of role and physical function, VAS, overall health, and overall QoL remaining stable. Clinical trial information: NCT03353753 .

Ripretinib (DCC-2618) was designed to inhibit the full spectrum of mutant KIT and PDGFRA kinases found in cancers and myeloproliferative neoplasms, particularly in gastrointestinal stromal tumors (GISTs), in which the heterogeneity of drug-resistant KIT mutations is a major challenge. Ripretinib is a "switch-control" kinase inhibitor that forces the activation loop (or activation "switch") into an inactive conformation. Ripretinib inhibits all tested KIT and PDGFRA mutants, and notably is a type II kinase inhibitor demonstrated to broadly inhibit activation loop mutations in KIT and PDGFRA, previously thought only achievable with type I inhibitors. Ripretinib shows efficacy in preclinical cancer models, and preliminary clinical data provide proof-of-concept that ripretinib inhibits a wide range of KIT mutants in patients with drug-resistant GISTs.

This systematic literature review with meta-analysis was conducted on the clinical efficacy and safety of interventions used in the treatment of chronic lymphocytic leukemia (CLL). We systematically searched databases (PubMed, Cochrane Library, and Embase; 1997 to August 2, 2012), conference abstracts, bibliographic reference lists, recent reviews, and Clinicaltrials.gov. Primary efficacy outcomes were objective response rate, progression-free survival, and overall survival. Safety end points were Grade 3/4 toxicities, serious adverse events, withdrawals because of toxicity, and deaths due to toxicity. Studies were selected if they were randomized controlled trials (RCTs) reporting on the efficacy or safety of relapsed or refractory CLL and if outcomes for CLL were reported separately from trials that included other lymphoid neoplasms. We used the Bucher method for conducting adjusted indirect comparisons within a meta-analysis. We identified 6 RCTs of pharmacologic treatment for relapsed/refractory CLL. The most common drugs investigated (alone or in combination) were fludarabine and cyclophosphamide. When reported, median overall survival ranged from 27.3 to 52.9 months, and overall response rate from 58% to 82%. Although meta-analysis of efficacy results was considered, details are not presented because only 3 studies qualified and the common comparator treatment was not clinically relevant. The relatively small number of RCTs, few overlapping treatment arms, and variability in end points studied make it difficult to formally compare therapies for relapsed/refractory CLL. Significant variability in RCT features presents a further challenge to meaningful comparisons. Additional well-designed RCTs are needed to fully understand the relative efficacy and safety of older and more recently developed therapies.

Background: DCC-3014 is an orally administered kinase inhibitor targeting the switch pocket of colony-stimulating factor 1 receptor (CSF1R). DCC-3014 exhibits approximately 100-fold selectivity from kinases homologous to CSF1R, such as KIT, and greater selectivity against 300 other human kinases. Tumor-associated macrophages (TAMs) are dependent on CSF1R kinase activity for proliferation and maintenance of the immunosuppressive phenotype. TAMs are known to enable tumor cells escape from immune surveillance. DCC-3014 is designed to exhibit an antitumor effect by inhibition of immunosuppressive TAMs or other CSF1R signaling-dependent pro-tumor activities. In addition, tenosynovial giant cell tumor (TGCT) is a rare, monoarticular disease known to be caused by the translocation in the CSF1 gene leading to overexpression of CSF1. Anti-CSF1R therapies have shown clinical activity in diffuse TGCT. Methods: This study is a multicenter, first-in-human study of DCC-3014 to determine a recommended Phase 2 dose (RP2D) or maximally tolerated dose (MTD) with a 3+3 dose escalation design and evaluate the safety, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of DCC-3014 in advanced solid tumors, including diffuse-type TGCT [NCT03069469]. Results: As of June 2, 2019, the study is ongoing in the dose escalation phase and has enrolled 32 patients with advanced solid tumors in 7 cohorts. The first cohort was initiated at 10 mg daily. Based on preliminary PK analysis from the first cohort, subsequent cohorts utilized a loading dose followed by a maintenance dosing schedule to achieve steady-state exposures more rapidly. The median age of patients was 61 years old and 69% were female with the median of 4 lines of prior anti-cancer treatment. No dose limiting toxicities (DLTs) have been seen in the assessed cohorts. Most commonly seen treatment-emergent adverse events (TEAEs >20%) were constipation (38%), vomiting (34%), diarrhea (31%), nausea (31%), decreased appetite (25%), abdominal pain (22%), and dyspnea (22%) whereas diarrhea, nausea and fatigue were reported as treatment-related AEs seen in >10% of all patients (13%). TEAEs were mostly Grade 1 or 2. Serious AEs (SAEs) were seen in 16 patients, none of which were related to DCC-3014. Exposure was approximately dose proportional. PD effects were seen for dose levels at 10 mg and above, and induction of the CSF1R ligand, CSF-1, was seen up to 148-fold from baseline. The RP2D or MTD has not been selected or reached. Conclusion: DCC-3014 in this study was generally well tolerated in patients with advanced solid tumors and showed approximately dose-proportional exposure and PD changes as expected. Further evaluation is ongoing to determine the RP2D or MTD. Data from the TGCT cohort will be presented at a future meeting. Citation Format: Matthew H Taylor, Stephen Leong, Ying Su, Cynthia B Leary, Xiaoyan Li, Keisuke Kuida, Rodrigo Ruiz-Soto, Todd Bauer. Phase 1 study of DCC-3014, an oral inhibitor of CSF1R, to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics in patients with advanced solid tumors, including diffuse-type tenosynovial giant cell tumor [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C087. doi:10.1158/1535-7163.TARG-19-C087

Background: Rebastinib is an orally administered, kinase inhibitor targeting the switch pocket of tunica interna endothelial cell kinase (TIE2). TIE2 is primarily expressed in endothelial cells, playing a role in angiogenesis. In addition, TIE2 is expressed in a subset of macrophages, TIE2 expressing macrophages (TEMs), which have pro-angiogenic, pro-metastatic, and immunosuppressive properties. Accumulating evidence suggests that chemotherapies, such as paclitaxel, increase the recruitment and activity of TEMs, leading to chemotherapy resistance. This study aims to investigate the efficacy of anti-TIE2 therapy against chemo-resistant advanced solid tumors. Methods: This is an open-label, Phase 1b/2, multicenter study with two parts. Part 1 evaluated two doses of rebastinib at 50 and 100 mg twice daily (BID) with paclitaxel administered weekly at 80 mg/m2 to determine the recommended phase 2 dose (RP2D) by enrolling at least 15 pts in each arm. The objective of Part 1 is to identify a recommended Phase 2 dose. Pts with locally advanced or metastatic solid tumors for which paclitaxel was considered appropriate treatment were enrolled. Part 2 has four disease-specific cohorts: triple-negative breast cancer, inflammatory breast cancer, platinum-resistant ovarian cancer and metastatic endometrial cancer to further evaluate the safety, tolerability and efficacy of the RP2D. This abstract focuses on data from Part 1. Results: A total of 43 pts were enrolled in Part 1 (24 pts at 50 mg BID and 19 pts at 100 mg BID) as of June 21, 2019. The median age was 61 years; 79% were female. Most frequent diagnoses were ovarian (11 pts), breast (8 pts) and endometrial cancer (7 pts). The median number of prior anti-cancer therapies was four (4). Median duration of treatment is 56 days. Treatment-emergent adverse events (TEAEs) were reported for 41 pts. Most TEAEs were previously observed in the rebastinib first-in-human study or were known AEs of paclitaxel. TEAEs >10% include mostly Grade (Gr) 1 or 2 fatigue (30%), constipation (21%), dry mouth (21%), nausea and alopecia (19% each), anemia and UTI (16%), hypokalemia, hypomagnesemia, peripheral neuropathy, and dyspnea (14% each), diarrhea, stomatitis, vomiting, sepsis, dysgeusia, rash and ALT elevation (12% each). Twenty-four pts experienced at least one ≥Gr 3 TEAE. Six pts had ≥Gr 3 AEs related to rebastinib. No significant difference in TEAEs was observed between the two dose levels. The RP2D was determined for rebastinib at 100 mg BID in combination with weekly paclitaxel at 80 mg/m2. Exposure of rebastinib was dose-proportional. Plasma TIE2 and its ligand, ANG2, were induced in a dose-dependent manner. Evidence of observed preliminary clinical activity in heavily pre-treated patients will be presented. Conclusion: Preliminary results demonstrated that the combination of rebastinib and paclitaxel was generally well tolerated. This combination is currently under evaluation in four disease-specific cohorts in Part 2. Clinical trial information: NCT03601897. Citation Format: Filip Janku, Michael Birrer, Debra Richardson, Christina Chu, Sanjay Goel, Ying Su, Bahar Matin, Keisuke Kuida, Rodrigo Ruiz-Soto, Erika Paige Hamilton. Phase 1b/2 study of rebastinib (DCC-2036) in combination with paclitaxel: Preliminary safety, efficacy, pharmacokinetics and pharmacodynamics in patients with advanced or metastatic solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B055. doi:10.1158/1535-7163.TARG-19-B055

Objective: Ripretinib (DCC-2618) is a kinase switch control inhibitor designed to broadly inhibit KIT and PDGFRA mutations. Based on clinical activity observed in heavily pretreated patients (pts) with GIST in a Phase 1 study (NCT02571036), ripretinib is under evaluation in two Phase 3 studies: INVICTUS (NCT03353753) in ≥4th-line pts and INTRIGUE (NCT03673501) in 2nd-line pts, each at the recommended dose of 150 mg once daily (QD). This abstract reports updated results from the escalation and expansion phases of the Phase 1 study for pts treated with ≥100 mg daily dose. Methods: The Phase 1 study includes a dose-escalation phase that tested oral ripretinib QD or twice daily (BID) in 28-day cycles, followed by an expansion phase with the recommended Phase 2 dose (RP2D) of 150 mg QD in 6 cohorts, including cohorts for pts with GIST based on prior regimens (2nd/ 3rd, 4th, and >4th-line). Local Response Evaluation Criteria in Solid Tumors (RECIST) response assessments were performed every 2 cycles and pts who progressed per RECIST in the expansion cohorts were allowed to dose escalate to 150 mg BID. Results: At a cut-off date of March 01, 2019, 179 pts with GIST in the escalation and expansion phases (median follow-up of 10.4 months; range, 0.1–32.3) were enrolled at dose levels of ≥100 mg daily with KIT-driven (169 pts), PDGFRA-driven (9 pts), or wild-type-driven GIST (1 pt). Of 178 pts with GIST treated at the ≥100 mg daily dose (1 pt was not included in the intent-to-treat population as the pt only participated in the food effect portion of the study), there were 37 2nd-line pts, 31 3rd-line pts, 60 4th-line pts, and 50 >4th-line pts. The objective response rate (ORR) by best response was 30% in 2nd-line pts (n=11; includes 3 unconfirmed responses), 23% in 3rd-line pts (n=7; includes 3 unconfirmed responses), and 11% in ≥4th-line pts (n=12; includes 4 unconfirmed responses); responses ≥4th-line include 15% in 4th-line pts (n=9; includes 4 unconfirmed responses) and 6% in >4th-line pts (n=3; includes no unconfirmed responses). In 2nd-line pts, the disease control rate (DCR) was 31% (n=9) at 52 weeks. The median progression-free survival (mPFS) was 42 weeks in 2nd-line pts, 40 weeks in 3rd-line pts, and 24 weeks in ≥4th-line pts (includes 30 weeks in 4th-line pts and 16 weeks in >4th-line pts). In 2nd-line pts, the median duration of response was 80 weeks and the median duration of treatment was 44 weeks. For any line, 13% of pts (n=24) experienced treatment-emergent adverse events (TEAEs) leading to study treatment discontinuation, 17% of pts (n=31) experienced TEAEs leading to dose reduction and 49% (n=88) had TEAEs leading to study drug interruption. Grade 3 or 4 TEAEs in >5% of pts were lipase increased (18%; n=33), anemia (11%; n=20), hypertension (7%; n=13), and abdominal pain (6%; n=11). Conclusion: In this Phase 1 study, ripretinib demonstrated encouraging clinical benefit (as measured by mPFS, ORR [best response] and DCR) and was generally well-tolerated in pts with GIST treated in the 2nd-line or later. Preliminary data from this Phase 1 study further supports testing in the ongoing Phase 3 study in 2nd-line GIST. Citation Format: Ping Chi, Filip Janku, Michael Heinrich, Kristen Ganjoo, Hans Gelderblom, Michael Gordon, Robin Jones, Albiruni Razak, Jonathan Trent, Margaret von Mehren, Simin Hu, Ying Su, Rodrigo Ruiz-Soto, Suzanne George. Updated results of phase 1 study of ripretinib (DCC-2618), a broad-spectrum KIT and PDGFRA inhibitor, in patients with gastrointestinal stromal tumor (GIST) by line of therapy (NCT02571036) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C077. doi:10.1158/1535-7163.TARG-19-C077

Objectives: Ripretinib is a novel, oral kinase switch control inhibitor of KIT and PDGFRα. Encouraging clinical benefit from the phase 1 dose escalation and expansion study as measured by ORR, DCR and PFS in 2nd, 3rd, and >4th line GIST patients with a favorable tolerability profile at doses >100 mg/day has been previously reported (ESMO 2018, abstract #1603O). It has been reported that more than 40% of GIST patients use acid-reducing agents. PPIs are the most potent acid-reducing agents that may impair the absorption of kinase inhibitors 1,2. This retrospective analysis aims to explore whether ripretinib can be used regardless of concomitant PPI use. Methods: The analysis assessed the impact of PPIs on the plasma concentration of ripretinib using PK data from the expansion cohort at the recommended Phase 2 dose of 150 mg QD. Plasma concentrations of ripretinib and its active metabolite DP-5439 obtained from patients who used or did not use PPIs were compared on Cycle 1 Day 1 (C1D1, n=106) and Day 15 (C1D15, n=102). Patients using PPIs were defined as those who continuously took PPIs for at least 4 days prior to C1D1 or C1D15. Patients who did not use PPIs were defined as those who did not take PPIs or any other acid-reducing agents during the study. Results: PK profiles were consistent between patients using and not using PPIs (Table 1), indicating a low likelihood of a clinically significant drug interaction between PPIs and ripretinib. Conclusions: This retrospective PK analysis provides supporting evidence that restriction of co-administration of PPIs with ripretinib may not be necessary. A dedicated drug interaction study is planned to provide a definitive assessment. References: 1. Smelick et al, Mol. Pharmaceutics 2013, 10, 4055−4062 2. Budha et al, Clin Pharmacol Ther. 2012, 92(2):203-13 Table 1.PK Exposure of Ripretinib and DP-5439 in Patients Using or not Using PPIsPK ConcentrationsRipretinib in ng/mL [mean (CV%)]DP-5439 in ng/mL [mean (CV%)]Ripretinib + DP-5439 in ng/mL [mean (CV%)]Using PPIsNot using PPIsUsing PPIsNot using PPIsUsing PPIsNot using PPIsC1D1 6 hr566 (58%) n=24670 (53%) n=82302 (64%) n=23297 (59%) n=82862 (54%) n=24975 (48%) n=82C1D15 pre-dose364 (79%) n= 24344 (63%) n=78960 (80%) n=24889 (86%) n=781350 (72%) n=241260 (75%) n=78C1D15 6 hr834 (51%) n=24871 (47%) n=731170 (69%) n=241060 (67%) n=732040 (53%) n=241960 (49%) n=73Notes: Table 1 is based on data from patients without a history of gastrectomy. A separate analysis in patients with gastrectomy will be published after sufficient data is obtained. Citation Format: Filip Janku, Michael Heinrich, Ping Chi, Albiruni Abdul Razak, Margaret von Mehren, Michael Gordon, Kristen Ganjoo, Jonathan Trent, Robin L. Jones, Hans Gelderblom, Kelli Running, Jing Wang, Rodrigo Ruiz-Soto, Suzanne George. Ripretinib (DCC-2618) pharmacokinetics (PK) in a Phase I study in patients with gastrointestinal stromal tumors (GIST) and other advanced malignancies: A retrospective evaluation of the PK effects of proton pump inhibitors (PPIs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT058.

TPS2666 Background: Rebastinib is a potent, orally administered, kinase switch control inhibitor selectively targeting the tunica interna endothelial cell kinase (TIE2). TIE2 is primarily expressed in endothelial cells and has critical roles in angiogenesis. In addition, TIE2 is highly expressed in a subset of macrophages, TIE2-expressing macrophages (TEMs), which are known to have proangiogenic, pro-metastatic, and immunosuppressive properties. Accumulating evidence suggests that chemotherapies, such as carboplatin, increase the recruitment and activity of pro-tumoral TEMs, leading to chemotherapy resistance. Taken together, investigation of rebastinib in combination with a chemotherapy such as carboplatin, one of the most commonly used agents across different tumor types, is warranted in advanced solid tumors. Methods: This study is an open-label, Phase 1b/2, multicenter study in patients with advanced or metastatic solid tumors. The study has two parts: the first part is the 3+3 dose escalation phase designed to evaluate the safety, tolerability and pharmacokinetics of 50 mg and 100 mg rebastinib twice daily in combination with carboplatin of AUC 5 or 6 administered once every three weeks to determine the recommended phase 2 dose (RP2D). Patients who have exhausted all therapies and for whom carboplatin is considered appropriate treatment will be enrolled. The second part is the dose expansion phase with three cohorts: previously treated breast cancer, recurrent, platinum-sensitive ovarian cancer, and malignant mesothelioma to evaluate the safety, tolerability, and efficacy of the RP2D. A Simon’s two-stage design will be used in the second part and initially up to 18 patients will be enrolled into each cohort. If more than 4 responses are observed, then the cohort will be expanded up to 33 patients. This trial is expected to enroll up to 117 patients in total, with approximately 18 patients in the first part and up to 99 patients in the second part. The study is currently open only in the US. Clinical trial information: NCT03717415.

Introduction: This randomized open-label phase II study evaluated the efficacy, safety, and tolerability of pazopanib in combination with pemetrexed compared with the standard cisplatin/pemetrexed doublet in patients with previously untreated, advanced, nonsquamous non–small-cell lung cancer. Methods: Patients were randomized (2:1 ratio) to receive pemetrexed 500 mg/m 2 intravenously once every 3 weeks plus either oral pazopanib 800 mg daily or cisplatin 75 mg/m 2 intravenously once every 3 weeks up to six cycles. All patients received folic acid, vitamin B12, and steroid prophylaxis. The primary endpoint was progression-free survival (PFS). Results: The study was terminated after 106 of 150 patients were randomized due to a higher incidence of adverse events leading to withdrawal from the study and severe and fatal adverse events in the pazopanib/pemetrexed arm than in the cisplatin/pemetrexed arm. At the time enrolment was discontinued, there were three fatal adverse events in the pazopanib/pemetrexed arm, including ileus, tumor embolism, and bronchopneumonia/sepsis. Treatment with pazopanib/pemetrexed was discontinued resulting in more PFS data censored for patients in the pazopanib/pemetrexed arm than those in the cisplatin/pemetrexed arm. There was no statistically significant difference between the pazopanib/pemetrexed and cisplatin/pemetrexed arms for PFS (median PFS, 25.0 versus 22.9 weeks, respectively; hazard ratio=0.75; 95% confidence interval, 0.43%–1.28%; p = 0.26) or objective response rate (23% versus 34%, respectively; 95% confidence interval, –30.6% to 7.2%; p = 0.21). Conclusion: The combination of pazopanib/pemetrexed in first-line treatment of non–small-cell lung cancer showed some antitumor activity but had unacceptable levels of toxicity.

Purpose This phase I expansion cohort study evaluated the safety and clinical activity of mirvetuximab soravtansine (IMGN853), an antibody–drug conjugate consisting of a humanized anti–folate receptor alpha (FRα) monoclonal antibody linked to the tubulin-disrupting maytansinoid DM4, in a population of patients with FRα-positive and platinum-resistant ovarian cancer. Patients and Methods Patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer received IMGN853 at 6.0 mg/kg (adjusted ideal body weight) once every 3 weeks. Eligibility included a minimum requirement of FRα positivity by immunohistochemistry (≥ 25% of tumor cells with at least 2+ staining intensity). Adverse events, tumor response (via Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1), and progression-free survival (PFS) were determined. Results Forty-six patients were enrolled. Adverse events were generally mild (≤ grade 2), with diarrhea (44%), blurred vision (41%), nausea (37%), and fatigue (30%) being the most commonly observed treatment-related toxicities. Grade 3 fatigue and hypotension were reported in two patients each (4%). For all evaluable patients, the confirmed objective response rate was 26%, including one complete and 11 partial responses, and the median PFS was 4.8 months. The median duration of response was 19.1 weeks. Notably, in the subset of patients who had received three or fewer prior lines of therapy (n = 23), an objective response rate of 39%, PFS of 6.7 months, and duration of response of 19.6 weeks were observed. Conclusion IMGN853 exhibited a manageable safety profile and was active in platinum-resistant ovarian cancer, with the strongest signals of efficacy observed in less heavily pretreated individuals. On the basis of these findings, the dose, schedule, and target population were identified for a phase III trial of IMGN853 monotherapy in patients with platinum-resistant disease.

Elevated folate receptor alpha (FRα) expression is characteristic of epithelial ovarian cancer (EOC), thus establishing this receptor as a candidate target for the development of novel therapeutics to treat this disease. Mirvetuximab soravtansine (IMGN853) is an antibody-drug conjugate (ADC) that targets FRα for tumor-directed delivery of the maytansinoid DM4, a potent agent that induces mitotic arrest by suppressing microtubule dynamics. Here, combinations of IMGN853 with approved therapeutics were evaluated in preclinical models of EOC. Combinations of IMGN853 with carboplatin or doxorubicin resulted in synergistic antiproliferative effects in the IGROV-1 ovarian cancer cell line in vitro. IMGN853 potentiated the cytotoxic activity of carboplatin via growth arrest and augmented DNA damage; cell cycle perturbations were also observed in cells treated with the IMGN853/doxorubicin combination. These benefits translated into improved antitumor activity in patient-derived xenograft models in vivo in both the platinum-sensitive (IMGN853/carboplatin) and platinum-resistant (IMGN853/pegylated liposomal doxorubicin) settings. IMGN853 co-treatment also improved the in vivo efficacy of bevacizumab in platinum-resistant EOC models, with combination regimens causing significant regressions and complete responses in the majority of tumor-bearing mice. Histological analysis of OV-90 ovarian xenograft tumors revealed that concurrent administration of IMGN853 and bevacizumab caused rapid disruption of tumor microvasculature and extensive necrosis, underscoring the superior bioactivity profile of the combination regimen. Overall, these demonstrations of combinatorial benefit conferred by the addition of the first FRα-targeting ADC to established therapies provide a compelling framework for the potential application of IMGN853 in the treatment of patients with advanced ovarian cancer.