Basket Trial of IDX-1197, a PARP Inhibitor, in Patients With HRR Mutated Solid Tumors (VASTUS)

TPS354 Background: BRCA1-Associated Protein 1 (BAP1) is a critical regulator of the cell cycle, cellular differentiation, cell death, and DNA damage response. It also acts as a tumor suppressor. Preclinical models demonstrate significant synthetic lethality in BAP1 mutant cell lines and patient xenografts when treated with PARP inhibitors, independent of underlying BRCA status, suggesting this mutation confers a BRCA-like phenotype. BAP1 is mutated, leading to a loss of functional protein, in up to 30% of cholangiocarcinomas as well as several other solid tumors. Methods: This phase 2, open-label, single arm multicenter study aims to exploit the concept of synthetic lethality with the use of the PARP inhibitor niraparib in pts with metastatic relapsed or refractory solid tumors. Eligible pts with measurable metastatic and incurable solid tumors are assigned to one of two cohorts: Cohort A (histology-specific): tumors harboring suspected BAP1 mutations including cholangiocarcinoma, uveal melanoma, mesothelioma or clear cell renal cell carcinoma with tissue available for BAP1 mutational assessment via NGS or Cohort B (histology-agnostic): tumors with known DNA damage response (DDR) mutations (Table) confirmed by CLIA-approved NGS. Other key eligibility criteria include age ≥18 years, adequate cardiac, renal, hepatic function and Eastern Cooperative Oncology Group performance status of 0 to 1. Pts with known BRCA1 or BRCA2 mutations or prior PARPi exposure are excluded. Pts receive niraparib 200-300mg daily (depending on weight and/or platelet count) continuously. Primary endpoint is objective response rate with secondary endpoints of PFS, OS, toxicity and exploratory biomarker determinations. Radiographic response by RECIST criteria is measured every 8 weeks while on treatment. Cohort A has fully enrolled. Cohort B enrollment continues to a maximum of 47 total evaluable subjects with expansion cohorts allowable for histologic or molecular subtypes meeting pre-specified responses. NCT03207347 Clinical trial information: NCT03207347. [Table: see text]

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Combination olaparib and durvalumab for patients with recurrent IDH-mutated gliomas.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e14026 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e14026-e14026

Author(s):

Ronald Ramos ◽

Seth Andrew Climans ◽

Ashley Adile ◽

Pegah Ghiassi ◽

Stephanie Baker ◽

...

Keyword(s):

Clinical Trial ◽

Cancer Cells ◽

Solid Tumors ◽

Group Performance ◽

Parp Inhibitor ◽

Objective Response ◽

Parp Inhibitors ◽

Solid Cancer ◽

Low Grade ◽

Idh Mutations

e14026 Background: Isocitrate dehydrogenase (IDH) mutations are frequently observed in low grade gliomas and secondary glioblastoma. Mutant IDH enzymes aberrantly convert α-ketoglutarate (αKG) to 2-hydroxyglutarate (2HG). Accumulation of 2HG inhibits αKG-dependent dioxygenases, many of which are involved in epigenetic regulation. This can lead to cellular dedifferentiation and tumor formation. IDH-mutated cancer cells exhibit defective homologous recombination repair, providing the rationale for investigating poly (adenosine 5’-diphophate-ribose) polymerase (PARP) inhibitors in these tumors. Blockade of programmed cell death ligand 1 (PD‐L1) re‐sensitizes PARP inhibitor treated cancer cells to T‐cell killing. We report the preliminary results of the glioma arm of a clinical trial of a PARP inhibitor, olaparib plus PD-L1 inhibitor, durvalumab, for IDH-mutated solid cancer. Methods: This is a single arm phase II basket study (NCT03991832). Patients with IDH-mutated solid tumors are divided into three cohorts; A: glioma; B: cholangiocarcinoma; C: all other solid tumors. Major eligibility criteria include IDH mutation by immunohistochemistry or sequencing, progressive disease with maximum two prior systemic therapies, Eastern Cooperative Oncology Group performance status (ECOG) 0 –1 and adequate organ function. Patients were excluded if they had received prior PARP inhibitors or anti-PD-1/PD-L1 antibodies. Patients were treated with olaparib 300 mg orally twice daily continuously and durvalumab 1500 mg IV every 4 weeks. Each cycle was 4 weeks. Tumor response was evaluated by MRI after every 2 cycles of study treatments using response evaluation criteria in solid tumors (RECIST). Results: As of Jan 2021, 9 patients were enrolled in Arm A, 7 men and 2 women. The median age was 42 years. Eight patients had IDH1 mutations and 1 had an IDH2 mutation. There were two patients with 1p/19q codeletion. Two patients had grade 2 tumors, four had grade 3, and three had grade 4 tumors. Median time since tumor diagnosis was 7 years. Objective response was seen in 1 patient with an IDH-mutated glioblastoma who remains on study treatments after 8 cycles. Six patients (67%) had tumor progression after two cycles. Two patients had stable disease as per RECIST but had clinical deterioration and did not continue the combined treatment. Common treatment emergent adverse events were all grade 1: fatigue (8 patients), nausea (6), abdominal pain (3), anemia (3), thrombocytopenia (3), and diarrhea (2). Median progression free survival was 2.5 months (range 1.9–8 months). Updated analysis and correlative studies will be presented at the meeting. Conclusions: Combination treatment with olaparib and durvalumab for patients with IDH-mutated glioma is well tolerated but appears to lack adequate antitumor activity. Clinical trial information: NCT03991832.

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Phase 1 Study of the Parp Inhibitor E7449 As a Single Agent in Patients with Advanced Solid Tumors or B-Cell Lymphoma

Annals of Oncology ◽

10.1093/annonc/mdu331.13 ◽

2014 ◽

Vol 25 ◽

pp. iv151 ◽

Cited By ~ 1

Author(s):

R. Plummer ◽

D. Dua ◽

N. Cresti ◽

A. Suder ◽

Y. Drew ◽

...

Keyword(s):

B Cell ◽

Solid Tumors ◽

Cell Lymphoma ◽

Phase 1 ◽

Parp Inhibitor ◽

Single Agent ◽

B Cell Lymphoma ◽

Advanced Solid Tumors ◽

Phase 1 Study

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A phase I study to determine the comparative bioavailability of two different oral formulations of the PARP inhibitor, olaparib (AZD2281), in patients with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2010.28.15_suppl.2599 ◽

2010 ◽

Vol 28 (15_suppl) ◽

pp. 2599-2599 ◽

Cited By ~ 14

Author(s):

L. R. Molife ◽

M. D. Forster ◽

M. Krebs ◽

T. Pwint ◽

M. R. Middleton ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Phase I Study ◽

Parp Inhibitor ◽

Advanced Solid Tumors ◽

Oral Formulations ◽

Comparative Bioavailability

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Phase I study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the poly(ADP-ribose) polymerase (PARP) inhibitor veliparib (ABT-888; V) in combination with irinotecan (CPT-11; Ir) in patients (pts) with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.15_suppl.3000 ◽

2011 ◽

Vol 29 (15_suppl) ◽

pp. 3000-3000 ◽

Cited By ~ 17

Author(s):

P. LoRusso ◽

J. J. Ji ◽

J. Li ◽

L. K. Heilbrun ◽

G. Shapiro ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Phase I Study ◽

Parp Inhibitor ◽

Advanced Solid Tumors

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A phase 1b study of the anti-PD-1 monoclonal antibody BGB-A317 (A317) in combination with the PARP inhibitor BGB-290 (290) in advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.3013 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 3013-3013 ◽

Cited By ~ 13

Author(s):

Michael Friedlander ◽

Tarek Meniawy ◽

Ben Markman ◽

Linda R. Mileshkin ◽

Paul R. Harnett ◽

...

Keyword(s):

Pancreatic Cancer ◽

Monoclonal Antibody ◽

Solid Tumors ◽

Phase 1 ◽

Parp Inhibitor ◽

Single Agent ◽

Advanced Solid Tumors ◽

Phase 1 Study ◽

Multiple Tumor ◽

Study Results

3013 Background: The release of tumor-associated antigens may enhance the response to immunotherapy. BGB-A317, a humanized IgG4 variant monoclonal antibody engineered to have no Fc gamma receptor binding, targets the programmed cell death-1 (PD-1) receptor. It is being developed in solid and hematologic malignancies at a dose of 200 mg IV Q3W. BGB-290, a potent inhibitor of PARP 1/2, is hypothesized to promote neoantigen release that will potentially increase the efficacy of BGB-A317. A phase 1 study identified 60mg BID as the recommended Phase 2 dose (RP2D) for BGB-290. This study consists of initial dose escalation to determine the maximum-tolerated dose (MTD), safety, PK profile, and preliminary anti-tumor activity of the combination, followed by expansion into ovarian, breast, prostate, gastric, bladder, pancreatic and small cell lung cancers. Methods: Cohorts of 6 -12 pts with advanced solid tumors were treated in each of 5 planned dose levels (DLs). In DLs 1-3, BGB-290 doses ranged between 20-60mg PO BID with BGB-A317 2mg/kg IV Q3W. In DLs 4 - 5, BGB-290 doses were 40 or 60 mg BID; A317 was given at 200 mg IV Q3W based on PK data from a single agent Phase 1 study. Results: As of 16 Jan 2017, 38 pts [median age 59 years (34-75)] were treated in DLs 1-4; enrollment to DL5 is ongoing. One DLT of persistent Gr 2 nausea was reported in DL 4. The most common adverse event (AE) considered related to both study drugs was fatigue (10.5%). Immune-related AEs were Gr 3 hypophysitis (n = 1), Gr 3 or 4 autoimmune hepatitis(n = 2), and Gr 2 elevated AST/ALT (n = 1). Decreases in tumor burden have been observed in 16 pts; 7 achieved a PR (5 with ovarian and one each with uterine and pancreatic cancer) and one CR was observed in ovarian cancer. Six pts had SD for > 6 months including 2 pts with pancreatic cancer who received BGB-A317+BGB-290 for 189 and 281 days. Plasma/serum exposure of BGB-290 and BGB-A317 were consistent with those in single-agent trials. Conclusions: BGB290 and BGB-A317 can be combined. Dose expansion in multiple tumor types is planned to commence in 2017 once the RP2D is determined. Clinical trial information: NCT02660034.

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A phase 1b study of the anti-PD-1 monoclonal antibody BGB-A317 (A317) in combination with the PARP inhibitor BGB-290 (290) in advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.5_suppl.48 ◽

2018 ◽

Vol 36 (5_suppl) ◽

pp. 48-48 ◽

Cited By ~ 7

Author(s):

Michael Friedlander ◽

Tarek Meniawy ◽

Ben Markman ◽

Linda R. Mileshkin ◽

Paul Harnett ◽

...

Keyword(s):

Monoclonal Antibody ◽

Autoimmune Hepatitis ◽

Solid Tumors ◽

Phase 1 ◽

Parp Inhibitor ◽

Single Agent ◽

Maximum Tolerated Dose ◽

Advanced Solid Tumors ◽

Phase 1 Study ◽

Study Results

48 Background: The release of tumor-associated antigens may enhance the response to immunotherapy. BGB-A317, a humanized IgG4 variant monoclonal antibody engineered to have no Fc gamma receptor binding, targets the programmed cell death-1 (PD-1) receptor. It is being developed in solid and hematologic malignancies at a dose of 200 mg IV Q3W. BGB-290, a potent inhibitor of PARP 1/2, is hypothesized to promote neoantigen release that may potentially increase the efficacy of BGB-A317. A phase 1 study identified 60 mg BID as the recommended Phase 2 dose (RP2D) for BGB-290. This study consists of initial dose escalation to determine the maximum-tolerated dose (MTD), safety, pharmacokinetic (PK) profile, and preliminary antitumor activity of the combination, followed by expansion into ovarian, breast, prostate, gastric, bladder, pancreatic and small cell lung cancers. Methods: Cohorts of 6–12 patients with advanced solid tumors were treated in each of 5 planned dose levels (DLs). In DLs 1–3, BGB-290 doses ranged between 20–60 mg PO BID with BGB-A317 2 mg/kg IV Q3W. In DLs 4–5, BGB-290 doses were 40 or 60 mg BID; A317 was given at 200 mg IV Q3W based on PK data from a single agent Phase 1 study. Results: As of 31 March 2017, 43 patients [median age 63 years (34–75)] were treated in DLs 1–5. Three patients experienced four dose-limiting toxicities: grade 2 nausea (DL4), grade 2 nausea and grade 2 vomiting (DL5), and grade 4 autoimmune hepatitis (DL5). MTD was identified as BGB-A317 200 mg IV Q3W + BGB-290 40 mg PO BID. The most common adverse event (AE) considered related to both study drugs was fatigue. Immune-related AEs of Grade ≥3 were elevated alanine aminotransferase/aspartate aminotransferase (n = 3), autoimmune hepatitis (n = 3), and hepatitis (n = 1). Complete or partial response was observed in 11 patients, 4 of whom had confirmed PR or CR. Plasma/serum exposure of BGB-290 and BGB-A317 were consistent with those in single-agent trials. Conclusions: The combination of BGB-A317 and BGB-290 was generally well tolerated in patients with advanced solid tumors. These results support the continuation of this trial with enrollment into the disease-specific cohorts. Clinical trial information: NCT02660034.

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