A Trial of Pamiparib With Tislelizumab in Patients With Advanced Tumours With Homologous Recombination Repair Defects (IMPARP-HRD)

  • STATUS
    Recruiting
  • End date
    Aug 1, 2025
  • participants needed
    60
  • sponsor
    Peter MacCallum Cancer Centre, Australia
Updated on 9 March 2022
platelet count
anticoagulants
EGFR
primary cancer
BRCA1
BRCA2

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

Details
Condition Cancer
Treatment tislelizumab, pamiparib
Clinical Study IdentifierNCT04985721
SponsorPeter MacCallum Cancer Centre, Australia
Last Modified on9 March 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

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
Continues to meet all the inclusion criteria as per the TRIAGE Framework protocol
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
Platelet count ≥ 100 x109/L
ALT ≤ 3.0 x the ULN, irrespective of the presence or absence of liver metastases
AST ≤ 3.0 x the ULN, irrespective of the presence or absence of liver metastases
Serum bilirubin ≤ 1.5 x ULN (On fractionation ≤ 90% of total bilirubin should be unconjugated
Total bilirubin must be <4 x ULN for patients with Gilbert's Syndrome)
Serum creatinine ≤ 1.5x ULN or eGFR ≥ 30 mL/min/1.73 m2 by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (appendix 5)
INR ≤ 1.5x ULN (≤2.5x ULN if on anticoagulants) 8. Patient has the ability to take oral medications without medical history of
malabsorption or other chronic gastrointestinal disease, or other conditions
that may harm compliance and/or absorption of the study treatment
\. WOCBP must agree to use a highly effective method of birth control for the
duration of
the study and for 6 months after the last dose of study treatment (see
Appendix 3), and have a negative serum pregnancy test within 7 days of study
registration
\. Non-sterile males and their female partners must agree to use a highly
effective
method of birth control for the duration of the study and for 6 months after
the last dose of study treatment. Non- sterile males must avoid sperm donation
for the duration of the study and for at least 6 months after the last study
drug
\. Female patient must agree not to breastfeed starting at screening and
throughout the
study period, and for 6 months after the final study drug administration
\. Patient is willing and able to comply with the protocol for the duration
of the study
including undergoing biopsies, treatment, and scheduled visits and examination
including follow up

Exclusion Criteria

One or more of the exclusion criteria as per the TRIAGE Framework protocol applies
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
Mean QTc ≥ 470 ms calculated from triplicate ECGs using Fredericia's Correction
Active autoimmune disease or history of autoimmune disease that may relapse, with the
following exceptions
Controlled type 1 diabetes
Hypothyroidism managed with no treatment other than with hormone replacement
therapy
Controlled celiac disease
Skin disease not requiring systemic treatment (e.g. vitiligo, psoriasis
alopecia)
Any other disease that is not expected to recur in the absence of external
triggering factors
Any condition that required systemic treatment with either corticosteroids (> 10 mg
daily of prednisone or equivalent) or other immunosuppressive medication within 2
weeks prior to registration, with the following exceptions
Adrenal replacement steroid (dose ≤ 10 mg daily of prednisone or equivalent)
Topical, ocular, intra-articular, intranasal, or inhalational corticosteroid with
minimal systemic absorption
Short course (≤ 7 days) of corticosteroid prescribed prophylactically or for the
treatment of a non- autoimmune condition
Positive HIV test at screening
Patients with active HBV (chronic or acute; defined as having a positive HBsAg test at
screening) or HCV Note: Patients with a past or resolved HBV infection (defined as the
presence of HBcAb and absence of HBsAg) are eligible. Patients positive for HCV
antibody are eligible only if polymerase chain reaction is negative for HCV RNA
Patients with severe chronic or active infections requiring systemic antibacterial
antifungal or antiviral therapy, including active tuberculosis and COVID-19
Patients with a history of interstitial lung disease, non-infectious pneumonitis or
uncontrolled systemic diseases, including diabetes, hypertension, pulmonary fibrosis
acute lung diseases, etc
History of non-viral hepatitis or cirrhosis
Any of the following cardiovascular criteria
Current evidence of cardiac ischemia
Current symptomatic pulmonary embolism
Acute myocardial infarction ≤ 6 months prior to study registration
Heart failure of New York Heart Association Classification III or IV (See
Appendix 6) ≤ 6 months prior to study registration
Grade ≥ 2 ventricular arrhythmia ≤ 6 months prior to study registration
History of cerebrovascular accident within 6 months before first dose of study
drugs
Has been administered a live vaccine within 4 weeks prior to registration
Known sensitivity to any component of pamiparib and/or tislelizumab
Clear my responses

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