A Trial of Pamiparib With Tislelizumab in Patients With Advanced Tumours With Homologous Recombination Repair Defects

NCT04985721 | Unknown Phase 2 DMC FDA Drug

• 1 other identifier: 20/044
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 3

Brief Summary

This study will describe the efficacy of pamiparib in combination with tislelizumab in patients with advanced tumours harbouring molecular profiles consistent with homologous recombination deficiency (HRD), agnostic of tumour origin. A tumour-agnostic approach has been adopted in this study due to the broad activity of PARP inhibitors across multiple tumour types. In addition, response to PARP inhibitors has been demonstrated in patients with genomic features associated with HRD, even in the absence of germline BRCA1 or BRCA2 mutations. These results suggest that the presence of HRD itself is the key predictive biomarker for PARP inhibitor efficacy. This paves the way for a precision-oncology, tumour-agnostic approach to patient selection for treatment, rather than the traditional tumour site-of-origin basis for which the current PARP inhibitor approvals exist. To investigate this, cohort A of this study includes patients with genomic features of HRD, but without a germline BRCA1 or BRCA2 mutation. Demonstration of clinical efficacy in this cohort will provide strong support to the tumour-agnostic, precision-oncology approach for patient selection for PARP inhibitor or PARP inhibitor combination treatment. This forms the primary objective of the study. The study will consist of two cohorts, broadly, cohort A - patients without a pathogenic BRCA1 or BRCA2 mutation but with other germline or somatic mutations in other HRD genes; cohort B- patients with a pathogenic BRCA1 or BRCA2

Conditions

Cancer

Outcome Measures

Primary Outcomes (1)

• Evaluation of clinical benefit rate (CBR) in patients with advanced tumours harbouring molecular profiles consistent with homologous recombination defeciency (HRD), without a known pathogenic germline BRCA1 or BRCA2 mutation.

  CBR, defined as the proportion of patients with either objective response (partial response (PR) + complete response (CR)) as best response, or stable disease (SD) at 12 weeks post registration, as determined by the Investigator by RECIST 1.1 in cohort A

  12 weeks after commencement of treatment

Secondary Outcomes (6)

• Efficacy of pamiparib in combination with tislelizumab in patients with advanced tumours harbouring molecular profiles consistent with HRD, and without a known pathogenic germline BRCA1 or BRCA2 mutation

  At the end of the study, approximately 4 years after the first participant commences treatment

• Efficacy of pamiparib in combination with tislelizumab in patients with advanced tumours harbouring molecular profiles consistent with HRD, and without a known pathogenic germline BRCA1 or BRCA2 mutation

  At the end of the study, approximately 4 years after the first participant commences treatment

• Efficacy of pamiparib in combination with tislelizumab in patients with advanced tumours harbouring molecular profiles consistent with HRD, and without a known pathogenic germline BRCA1 or BRCA2 mutation

  At the end of the study, approximately 4 years after the first participant commences treatment

• Evaluation of CBR of pamiparib in combination with tislelizumab in patients with advanced tumours harbouring molecular profiles consistent with HRD (independent of germline BRCA1 or BRCA2 mutation status)

  12 weeks post commencement of treatment

• Severity of Treatment -Emergent Events (Safety of pamiparib in combination with tiselizumab)

  At the end of the study, approximately 4 years after the first participant commences treatment

Study Arms (1)

Pamiparib and Tiselizumab

EXPERIMENTAL

Drug: Pamiparib; Drug: Tislelizumab

Interventions

Pamiparib DRUG

40 mg orally twice a day

Pamiparib and Tiselizumab

Tislelizumab DRUG

200 mg IV every 21 days

Pamiparib and Tiselizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Have provided written informed consent
• Male or female ≥ 18 years of age
• Patient has documentation of at least 1 of the following genomic features associated with HRD
• Cohort A - any of:
• A germline or somatic genetic alteration that is known or suspected to be deleterious in one of the following HR-related genes (ATM, CDK12, PALB2, ARID1A, ATRX, BLM, BARD1, BRIP1, CHEK1, CHEK2, FANCA, FANCF, FANCG, FANCI, FANCL, FANCM, MSH2, NBN, RAD50, RAD51C, RAD51D, WRN)
• A somatic genetic alteration that is known or suspected to be deleterious in BRCA1 or BRCA2
• A prevalent mutational signature 3 as determined by WGS (≥ 20% of total mutations attributed)
• The presence of a positive HRD status using a NGS assay that includes assessment for genomic instability
• Cohort A excludes high grade serous ovarian cancer, TNBC, and prostate cancer
• Cohort B - a pathogenic germline BRCA1 or BRCA2 mutation Note: Genomic features associated with HRD must have been determined from a sample obtained ≤ 12 months before the date of registration into this study with the exception of germline genetic alterations which can have been determined from a sample obtained at any time.
• Patient agrees to the collection and use of their fresh tumour biopsy sample during screening for WGS Note: A fresh tumour biopsy not required for patients who have had WGS performed within 12 months prior to registration to the study
• Measurable disease, as defined by RECIST 1.1 (see Appendix 2)
• Adequate haematological and end-organ function, defined by the following laboratory results obtained within 7 days prior to registration, independent of blood or platelet transfusion within 2 weeks:
• Haemoglobin ≥ 90 g/L
• ANC ≥ 1.5x109/L

You may not qualify if:

• Any previous treatment with a PARP inhibitor
• Note: Prior immune checkpoint blockade is permitted provided all the criteria below are met:
• Patients must not have received the immune checkpoint blockade within 28 days of study registration
• Patients must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy
• All AEs while receiving prior immunotherapy must have completely resolved or resolved to grade
• prior to screening for this study. Patients with an endocrine AE due to immunotherapy are permitted provided they are stably maintained on appropriate replacement therapy and are asymptomatic
• Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if re-challenged, and not require maintenance doses of \> 10 mg prednisolone or equivalent per day
• Any unresolved toxicity (≥CTCAE grade 2) from previous anti-cancer therapy, with the exception of alopecia Note: Patients with irreversible toxicity that is not reasonably expected to be exacerbated by the study treatment (e.g. hearing loss, peripheral neuropathy) are eligible
• Treatment with strong CYP3A inducers within 10 days (or ≤ 5 half-lives, whichever is shorter) prior to registration. Known need for treatment with strong CYP3A4 inducers during study treatment.
• Symptomatic or current history of actively progressing CNS metastases. Patients with a history of treated CNS lesions are eligible, provided that all of the following criteria are met:
• Measurable disease per RECIST 1.1 must be present outside the CNS
• In patients who have received CNS-directed therapy, there is no clinical evidence of interim progression between completion of CNS-directed therapy and registration to the study (radiological re-assessment is not required)
• The patient has not received radiotherapy within 14 days prior to registration Note: Anticonvulsant therapy at a stable dose is permitted
• Note: Patients with asymptomatic brain metastases in which CNS-directed therapy is not indicated are eligible
• History of leptomeningeal disease

Sponsors & Collaborators

• Peter MacCallum Cancer Centre, Australia: lead

Study Sites (3)

St Vincent's Hospital

Fitzroy, Victoria, 3065, Australia

RECRUITING

Austin Hospital

Heidelberg, Victoria, 3084, Australia

RECRUITING

Peter MacCallum Cancer Centre

Melbourne, Victoria, 3000, Australia

RECRUITING

MeSH Terms

Conditions

Neoplasms

Interventions

pamiparib; tislelizumab

Study Officials

• Stephen Luen, MBBS

  Peter MacCallum Cancer Institute

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Stephen Luen, MBBS

CONTACT

+61 3 8559 5000; stephen.luen@petermac.org

Jayesh Desai, MBBS

CONTACT

+61 8559 8339; jayesh.desai@petermac.org

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 28, 2021
• First Posted: August 2, 2021
• Study Start: February 24, 2022
• Primary Completion: August 1, 2025
• Study Completion: August 1, 2025
• Last Updated: March 15, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will not share

Locations

AU (3)