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A phase 1b dose escalation study of ipafricept (OMP54F28) in combination with paclitaxel and carboplatin in patients with recurrent platinum-sensitive ovarian cancer.

ABSTRACT: OBJECTIVES:The WNT pathway is an important oncologic driver of epithelial ovarian cancer (EOC). The first-in-class recombinant fusion protein ipafricept (IPA) blocks Wnt signaling through binding of Wnt ligands. This phase Ib trial was designed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RPh2) for IPA in combination with taxane and platinum therapy (C/P). METHODS:Dose escalation started with a standard 3?+?3 design for IPA/C/P with q3w intravenous IPA on Day 1, in cycles 1 to 6 with C (AUC?=?5?mg/ml·min) and P (175?mg/m2). For enhanced bone safety the trial was revised to 6-patient cohorts with a q3w regimen of IPA on Day 1 and C/P on Day 3 (IPA???C/P). RESULTS:37 patients have been treated; 30 of whom were treated following protocol revision to q3w IPA(D1)???C/P(D3) (2 & 4?mg/kg). IPA-related TEAEs that occurred in ?15% included: fatigue (40%); nausea (35%); diarrhea and decreased appetite (22%) each; dysgeusia (19%); and vomiting (16.2%). 22% reported ?1 IPA related TEAE Grade ?3 the most common of which was neutropenia at 16%. There were no DLTs; the MTD was not reached. The maximum administered dose based on bone safety was 6?mg/kg. The overall response rate (ORR) was 75.7%. Median PFS was 10.3?months (95% CI 8.5-14.2) and OS 33?months (95% CI 23.4-NR). CONCLUSIONS:IPA is well tolerated in combination with sequential C/P. ORR, PFS and OS are comparable to historical data but bone toxicity at efficacy doses of this particular Wnt inhibitor limit further development in EOC.

SUBMITTER: Moore KN

PROVIDER: S-EPMC7397408 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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A phase 1b dose escalation study of ipafricept (OMP54F28) in combination with paclitaxel and carboplatin in patients with recurrent platinum-sensitive ovarian cancer.

Moore Kathleen N KN Gunderson Camille C CC Sabbatini Paul P McMeekin D Scott DS Mantia-Smaldone Gina G Burger Robert A RA Morgan Mark A MA Kapoun Ann M AM Brachmann Rainer Karl RK Stagg Robert R Farooki Azeez A O'Cearbhaill Roisin E RE

Gynecologic oncology 20190604 2

<h4>Objectives</h4>The WNT pathway is an important oncologic driver of epithelial ovarian cancer (EOC). The first-in-class recombinant fusion protein ipafricept (IPA) blocks Wnt signaling through binding of Wnt ligands. This phase Ib trial was designed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RPh2) for IPA in combination with taxane and platinum therapy (C/P).<h4>Methods</h4>Dose escalation started with a standard 3 + 3 design for IPA/C/P with q3w intravenous I ...[more]

PMID: 31174889

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Project description:Lessons learnedDespite involvement of PI3K pathway activation in tumorigenesis of solid tumors, single-agent PI3K inhibitors have shown modest clinical activity.Preclinical evidence suggests that combining PI3K pathway inhibitors and chemotherapy can enhance antitumor effects.In patients with solid tumors, the PI3K inhibitor pilaralisib had a favorable safety profile but did not enhance the antitumor activity of paclitaxel plus carboplatin.Further clinical evaluation is warranted to identify effective combination strategies with PI3K pathway inhibitors.BackgroundPilaralisib (SAR245408) is an oral, pan-class I phosphoinositide 3-kinase (PI3K) inhibitor. This phase I dose-escalation study evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics of pilaralisib in capsule and tablet formulations, administered in combination with paclitaxel and carboplatin in patients with advanced solid tumors.MethodsA 3 + 3 design was used. Pilaralisib was administered once daily (QD); paclitaxel (up to 175 mg/m2) and carboplatin (up to area under the curve [AUC] of 6) were administered on day 1 of 21-day cycles. An MTD expansion cohort of patients with endometrial carcinoma was included.ResultsFifty-eight patients were enrolled. Six patients (10.3%) had dose-limiting toxicities, of which only rash (two patients, 3.4%) occurred in more than one patient. The MTD of pilaralisib tablets in combination with paclitaxel and carboplatin was determined to be 200 mg QD. The most frequently reported adverse events (AEs) of any grade were neutropenia (67.2%) and thrombocytopenia (67.2%). PK data showed no interaction between pilaralisib and paclitaxel/carboplatin. Tumor tissue showed moderate inhibition of PI3K and mitogen-activated protein kinase (MAPK) pathways. Seven of 52 evaluable patients had a partial response (PR; 13.5%).ConclusionPilaralisib had a favorable safety profile but did not enhance the antitumor activity of paclitaxel plus carboplatin in solid tumors. The Oncologist 2017;22:377-378.

Project description:BackgroundAnti-programmed death 1 (PD1)/programmed cell death ligand 1 (PD-L1) therapies have shown modest activity as monotherapy in recurrent ovarian cancer. Platinum chemotherapies induce T-cell proliferation and enhance tumor recognition. We assessed activity and safety of pembrolizumab with carboplatin in recurrent platinum-resistant ovarian cancer.Patients and methodsThis phase I/II, single-arm clinical trial studied concurrent carboplatin and pembrolizumab in recurrent platinum-resistant ovarian, fallopian tube, and primary peritoneal cancer. Primary platinum refractory patients were excluded. Patients were treated after progression on subsequent non-platinum systemic therapy after becoming platinum resistant or refractory. Pembrolizumab 200 mg was given on day 1 and carboplatin area under the curve 2 on days 8 and 15 of a 3-week cycle until progression. Imaging was assessed by blinded independent review. PD-L1 expression was assessed by immunohistochemistry. Flow cytometry on peripheral blood mononuclear cells was performed for CD3, CD4, CD8, PD1, CTLA4 and Ki67.ResultsThe most common treatment-related adverse events were lymphopenia (18%) and anemia (9%) with most being grade 1 or 2 (93%). Of 29 patients treated, 23 patients were evaluable for best objective response: 10.3% (95% CI 2.2 to 27.4) had partial response (PR), 51.7% (95% CI 32.5 to 70.6) had stable disease (SD). 56.5% of patients had decreases in target lesions from baseline. All PD-L1-positive patients achieved PR (3/7, 42.8%) or SD (4/7, 57.2%). Median progression-free survival was 4.63 months (95% CI 4.3 to 4.96). Median OS was 11.3 months (95% CI 6.094 to 16.506). Peripheral CD8+PD1+Ki67+ T cells expanded after 3 (p=0.0015) and 5 (p=0.0023) cycles. CTLA4+PD1+CD8+ T cells decreased through the course of treatment up to the 12th cycle (p=0.004). When stratified by ratio of peripheral CD8+PD1+Ki67+ T cells to tumor burden at baseline, patients with a ratio ≥0.0375 who had a significantly longer median OS of 18.37 months compared with those with a ratio <0.0375 who had a median OS of 8.72 months (p=0.0099). No survival advantage was seen with stratification by tumor burden alone (p=0.24) or by CD8+PD1+Ki67+ T cells alone (p=0.53).ConclusionsPembrolizumab with carboplatin was well-tolerated and active in recurrent platinum-resistant ovarian cancer. A ratio of peripheral T-cell exhaustion to radiographic tumor burden may identify patients more likely to benefit from this chemoimmunotherapy.Trial registration numberNCT03029598.

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Dataset Information

A phase 1b dose escalation study of ipafricept (OMP54F28) in combination with paclitaxel and carboplatin in patients with recurrent platinum-sensitive ovarian cancer.

Publications

A phase 1b dose escalation study of ipafricept (OMP54F28) in combination with paclitaxel and carboplatin in patients with recurrent platinum-sensitive ovarian cancer.

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