Abstract CT234: VASTUS - a phase 1b/2a basket trial of a new PARP inhibitor, IDX-1197, including PARP inhibitor resistant cohort

TPS5089 Background: Approved treatments for mCRPC (eg, enzalutamide and docetaxel) may increase programmed death ligand 1 (PD-L1) expression and facilitate neoantigen release. In phase 1b and 1/2 trials, pembro, an anti–PD-1 antibody, has produced antitumor responses in previously treated mCRPC as monotherapy and in combination with enzalutamide. Olaparib, a PARP inhibitor, has shown activity in mCRPC with DNA-repair defects. The nonrandomized, multicohort, open-label KEYNOTE-365 study (NCT02861573) will evaluate the safety and efficacy of pembro with olaparib (cohort A), docetaxel + prednisone (cohort B), or enzalutamide (cohort C) in mCRPC. Methods: Cohort allocation depends upon prior treatment: cohort A requires prior docetaxel (treatment with 1 other chemotherapy and ≤2 second-generation hormonal manipulations is allowed); cohort B requires prior abiraterone acetate or enzalutamide (but not both); cohort C requires prior abiraterone acetate. Additional eligibility criteria include confirmed prostate adenocarcinoma, disease progression (PD) ≤6 months before screening, ongoing androgen deprivation (serum testosterone < 50 ng/dL), and provision of nonirradiated tumor sample. Pembro 200 mg will be given every 3 weeks (Q3W) with either olaparib 400 mg twice daily (cohort A), docetaxel 75 mg/m2 Q3W + prednisone 5 mg twice daily (cohort B), or enzalutamide 160 mg once daily (cohort C). Pembro treatment will continue for up to 35 cycles or until PD or unacceptable adverse events (AEs). Patients in cohort B may receive a maximum of 10 cycles of docetaxel + prednisone. Patients who discontinue 1 of 2 drugs in a combination because of a treatment-related AE may continue to receive the other drug until PD. Response will be evaluated by prostate-specific antigen (PSA) levels Q3W and by imaging Q9W for the first year and Q12W thereafter. Primary end points are safety and PSA response rate (decline of ≥50% from baseline twice ≥3 weeks apart). Secondary end points include time to PSA progression, progression-free survival, overall survival, and overall response rate. Enrollment will continue until 70 patients are enrolled for each cohort. Clinical trial information: NCT02861573.

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IOLite: Multipart, phase 1b, dose-finding study of the PD-1 inhibitor dostarlimab in combination with the PARP inhibitor niraparib ± bevacizumab (bev), or with platinum-based chemotherapy ± bev for advanced cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.2560 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 2560-2560 ◽

Cited By ~ 1

Author(s):

Nashat Y. Gabrail ◽

Alberto Bessudo ◽

Erika Paige Hamilton ◽

Jasgit C. Sachdev ◽

Manish R. Patel ◽

...

Keyword(s):

Solid Tumors ◽

Parp Inhibitor ◽

Complete Response ◽

Dose Finding ◽

Open Label ◽

Part D ◽

Part C ◽

Platinum Based Chemotherapy ◽

Finding Study ◽

Phase 1B

2560 Background: Novel combinations of drugs may overcome resistance in patients (pts) with solid tumors who had progressed on standard therapy. Methods: IOLite (NCT03307785) is a multicenter, open label, multipart study to determine dosing and evaluate safety and efficacy of dostarlimab in combination with approved therapies in pts with advanced solid tumors. Pts were enrolled in each part based on tumor histology, prior treatment (tx) history, and physician preference. Primary endpoint is dose-limiting toxicities (DLTs) deemed as tx-related per investigator, and safety and tolerability of the combination. Tumor responses were assessed per RECIST v1.1. Results: Parts A-D (see Table) are fully enrolled. One complete response was reported in part B (endometrial); confirmed partial responses in part A (ovarian, small cell lung [SCLC], gastrointestinal stromal [GIST]); part B (breast [2], bladder, SCLC); part C (prostate, fallopian tube), and part D (endometrial, non-SCLC). Stable disease was reported in part A (colorectal, prostate [2], breast, GIST, gastric); part B (SCLC, squamous cell, head and neck, prostate); part C (pancreatic, ovarian, GIST, breast [2], liver, endometrial); part D (ovarian, head & neck, cholangiocarcinoma). At data cutoff, 24 pts remain on treatment. PK’s of dostarlimab and niraparib (nir) were not altered by any of the combination agents tested. Conclusions: Dostarlimab is well tolerated in combination with nir ± bev, or carbo-pac ± bev. Preliminary efficacy data show responses in various histologies. No new safety signals were identified. Clinical trial information: NCT03307785. [Table: see text]

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Phase 1b/2 SEASTAR trial: Safety, pharmacokinetics, and preliminary efficacy of the poly(ADP)-ribose polymerase (PARP) inhibitor rucaparib and angiogenesis inhibitor lucitanib in patients with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.3102 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 3102-3102

Author(s):

Ecaterina Elena Dumbrava ◽

Geoffrey Shapiro ◽

Johanna C. Bendell ◽

Timothy A. Yap ◽

Rinath Jeselsohn ◽

...

Keyword(s):

Solid Tumors ◽

Parp Inhibitor ◽

Specific Antigen ◽

Angiogenesis Inhibitor ◽

Parp Inhibition ◽

Pharmacokinetic Data ◽

Advanced Solid Tumors ◽

Immunological Mechanisms ◽

Phase 1B ◽

Grade 3

3102 Background: Lucitanib is an oral, potent tyrosine kinase inhibitor that selectively inhibits VEGFR1–3, PDGFRα/β, and FGFR1–3. In preclinical studies, antitumor activity of rucaparib is enhanced by lucitanib through antiproliferative, antiangiogenic, and immunological mechanisms. We hypothesize that combining lucitanib and rucaparib is tolerable and can induce a higher hypoxic state and homologous recombination repair deficiency that may lead to greater sensitivity to PARP inhibition. Methods: Patients with advanced solid tumors who had ≥1 prior line of therapy were eligible. Patients with BRCA1/2-mutated ovarian cancer must have received prior PARP inhibitor. Rucaparib and lucitanib were escalated using a 3+3 phase 1b dose-escalation design from starting doses of 300 mg BID and 4 mg QD, respectively. Dose-limiting toxicities (DLTs) were assessed during the first 28 days of treatment. Plasma samples were collected for pharmacokinetic analyses. Genomic alterations were identified by local testing, or through central testing of plasma or tumor tissue. Results: As of February 1, 2021, 16 patients were treated with rucaparib + lucitanib and included in the analyses (Table). Patients had a median of 4 prior therapies; 1 patient had prior PARP inhibitor (olaparib) treatment. Median time on treatment was 58.5 days, with 2 patients ongoing as of the data cutoff date. A DLT of grade 3 proteinuria was seen in Cohort 1; no other DLTs have been reported. Across all cohorts, the most common any-grade treatment-emergent adverse events were nausea (n=9; grade ≥3, n=1), hypertension (n=8; grade ≥3, n=2) and ALT/AST increased (n=7; grade ≥3, n=3). Initial pharmacokinetic data indicated no drug interactions between the 2 agents. To date, 1 patient in Cohort 1 with PALB2-mutated advanced endometrial cancer had a confirmed partial response per RECIST v1.1, lasting 30 weeks; 6 patients had RECIST v1.1 stable disease (SD), including 1 patient each in Cohorts 1 and 3 with SD for ≥16 weeks. In addition, 1 patient in Cohort 2 with BRCA2-mutated castration-resistant prostate cancer continued to receive treatment despite initial progressing bone metastases, resulting in a prostate-specific antigen response (≥50% change) lasting 16 weeks and a best change in sum of target lesions of −46.3%. Conclusions: Initial findings suggest that rucaparib + lucitanib has an acceptable safety profile. The safety and efficacy of the combination are being further evaluated. Clinical trial information: NCT03992131. [Table: see text]

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Phase 1b dose expansion and translational analyses of olaparib in combination with the oral AKT inhibitor capivasertib in recurrent endometrial, triple negative breast, and ovarian, primary peritoneal, or fallopian tube cancer

10.1101/2021.04.13.21255421 ◽

2021 ◽

Author(s):

Shannon N Westin ◽

Marilyne Labrie ◽

Jennifer Litton ◽

Aurora Blucher ◽

Yong Fang ◽

...

Keyword(s):

Endometrial Cancer ◽

Fallopian Tube ◽

Triple Negative ◽

Mapk Pathway ◽

Parp Inhibitor ◽

Therapy Resistance ◽

Akt Inhibitor ◽

Fallopian Tube Cancer ◽

Peritoneal Cancer ◽

Phase 1B

Background: Combining poly (ADP-ribose) polymerase (PARP) with phosphatidylinositol-3-kinase (PI3K) pathway inhibitors is supported by strong preclinical rationale. We sought to assess safety and determine a recommended phase 2 dose (RP2D) for PARP inhibitor olaparib combined with the AKT inhibitor, capivasertib, and evaluate molecular markers of response and resistance. Methods: As part of a larger phase 1b trial, we performed a safety lead in of olaparib and capivasertib followed by expansion (n=24) in endometrial, triple negative breast, ovarian, fallopian tube, or peritoneal cancer. Olaparib 300mg orally twice daily and capivasertib orally twice daily on a four day on three day off schedule was evaluated. Two dose levels (DL) were planned: capivasertib 400mg (DL1); capivasertib 320mg (DL-1). Patients underwent biopsies at baseline and after 28 days. Findings: 38 patients were enrolled. 7 (18%) patients had known germline BRCA1/2 mutations. The first two patients on DL1 experienced dose limiting toxicities (DLTs) of diarrhea and vomiting in absence of maximum supportive care. No DLTs were observed on DL-1 (n=6), therefore, DL1 was re-explored (n=6) with no DLTs, confirming this as RP2D. Most common treatment-related grade 3 or 4 adverse events were anemia (23.7%) and leukopenia (10.5%). Of 32 subjects evaluable for response, 6 (19%) had partial response (PR) with a PR rate of 44.4% in endometrial cancer. Seven (22%) additional patients had stable disease greater than 4 months. Tumor analysis demonstrated strong correlation between response and immune activity, as well as alterations in cell cycle and DNA damage response genes. Therapy resistance was associated with receptor tyrosine kinase (RTK) and RAS-MAPK pathway activity, as well as metabolism and epigenetics. Interpretation: The combination of olaparib and capivasertib is well tolerated and demonstrates evidence of durable activity in women's cancers, with particularly promising response in endometrial cancer. Importantly, tumor samples acquired pre and on-therapy can help predict patient benefit.

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Abstract #796012: Phase 1B Evaluation of the Pharmacokinetics and Pharmacodynamics of Abaloparatide Solid Microstructured Transdermal System in Postmenopausal Women with Low Bone Mineral Density

Endocrine Practice ◽

10.1016/s1530-891x(20)39452-0 ◽

2020 ◽

Vol 26 ◽

pp. 44-45

Author(s):

Joanna Rega

Keyword(s):

Bone Mineral Density ◽

Postmenopausal Women ◽

Bone Mineral ◽

Pharmacokinetics And Pharmacodynamics ◽

Mineral Density ◽

Low Bone Mineral Density ◽

Phase 1B

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PARP inhibitor pick-me-up

Nature Reviews Drug Discovery ◽

10.1038/d41573-019-00174-w ◽

2019 ◽

Vol 18 (11) ◽

pp. 814-814 ◽

Cited By ~ 1

Author(s):

Asher Mullard

Keyword(s):

Parp Inhibitor

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Neu diagnostiziertes Ovarialkarzinom

Onkologische Welt ◽

10.1055/a-0867-9156 ◽

2019 ◽

Vol 10 (03) ◽

pp. 113-113

Author(s):

Susanne Krome

Keyword(s):

Parp Inhibitor

Nach einer zytoreduktiven Operation und Chemotherapie erleiden 70 % der Patientinnen mit Ovarialkarzinomen innerhalb von 3 Jahren ein Rezidiv. Der PARP-Inhibitor Olaparib war bei Frauen mit BRCA1/2-Mutation und platinsensitiven Rückfällen eine effektive Erhaltungstherapie. Die SOLO1-Studie belegt die Wirksamkeit von Olaparib nun auch bei neu diagnostizierten Karzinomen.

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