Study Evaluating the Efficacy of a Double Immunotherapy Combined With Olaparib in Patients With Solid Cancers and Carriers of Homologous Recombination Repair Genes After Olaparib Treatment

  • STATUS
    Recruiting
  • End date
    Jun 10, 2029
  • participants needed
    270
  • sponsor
    Centre Georges Francois Leclerc
Updated on 31 May 2021

Summary

The study propose to generate a clinical trial based on precision medicine to evaluate the use of immunotherapy in patients with altered homologous recombination repair genes and without progression after prior targeted therapy.

Description

With the development of cost effective and rapid technology of genome sequencing, precision medicine becomes a new way to think oncology. Current targets involve mainly tyrosine kinase, but DNA repair machinery could also be targetable. Some of DNA repair aberrations have been associated with sensitivity to platinum and poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors like Olaparib, suggesting that treatment with a PARP inhibitor may exploit a synthetic lethal interaction when the presence of alteration of the homologous repair pathway was observed. PARP is involved in multiple aspects of DNA repair, and the PARP inhibitor Olaparib has recently been approved for treating ovarian cancers with BRCA1/2 mutations. In addition, it showed that using a high-throughput, next-generation sequencing assay in prostate cancer, detection of genomic alteration in genes involved in homologous repair pathway BRCA2, ATM, BRCA1, PALB2, CHEK2, FANCA, and HDAC2, is associated with response to olaparib. Thus demonstrating the clinical validation of the usage of precision medicine to position PARP inhibitor like olaparib in different cancer types based on molecular analysis.

Preclinical studies showed DNA damage promotes neoantigen expression. It is possible that increased DNA damage by PARPi would yield greater mutational burden and expand neoantigen expression, leading to greater immune recognition of the tumor. PARPi is also associated with immunomodulation. The PARPi talazoparib increases the number of peritoneal CD8+ T cells and natural killer cells and increases production of interferon (IFN)- and tumor necrosis factor- in a BRCA1-mutated ovarian cancer xenograft model. Hence, addition of PARPi to immune checkpoint blockade could complement the clinical benefit of immune checkpoint inhibition.

Such high level of mutation results in high number of neoantigen and antitumor immune response thus given the rational to use immunotherapy to target such type. A recent paper validate this strategy using the anti PD-1 pembrolizumab Some case reports suggest also that other mutations that induce hypermutated tumor (POLD, POLE, or MYH) could gain benefit from anti PD-1 therapy. Additional DNA repair machinery dysfunction may lead to accumulation of mutations. And such level of mutations could induce better response to immunotherapy. In the lung non-small cell setting high mutation rate were associated with better efficacy of both nivolumab and pembrolizumab.

Details
Condition Immunotherapy, immunotherapies
Treatment olaparib, durvalumab, tremelimumab
Clinical Study IdentifierNCT04169841
SponsorCentre Georges Francois Leclerc
Last Modified on31 May 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

\. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer
treatment. Concurrent use of hormonal therapy for non-cancer-related
conditions (e.g., hormone replacement therapy) is acceptable
\. Radiotherapy treatment to more than 30% of the bone marrow or with a wide
field of radiation within 4 weeks of the first dose of study drug
Radiotherapy (non-palliative) within 21 days prior the first dose of study
drug or within 6 weeks for therapeutic doses of MIBG or craniospinal
irradiation. Palliative RT (which would be <30% of the bone marrow) to non-
target lesions is allowed
\. Major surgical procedure within 28 days prior to the first dose of
olaparib and patients must have recovered from any effects of any major
surgery
\. Patients unable to swallow orally administered medication and patients
with Impairment of gastrointestinal (GI) function or GI disease that may
significantly alter drug absorption of oral drugs
\. History of allogenic organ, bone marrow or double umbilical cord blood
transplantation
\. Active or prior documented autoimmune or inflammatory disorders
\. Uncontrolled intercurrent illness or patient considered a poor medical
risk due to a serious, uncontrolled medical disorder, including but not
limited to, ongoing or active infection, symptomatic congestive heart failure
\. Currently taking medications with known risk of prolonging the QT
interval or inducing Torsades de Pointes
\. Concomitant use of known strong or moderate CYP3A inducers
\. Resting ECG indicating uncontrolled, potentially reversible cardiac
conditions or patients with congenital long QT syndrome
\. Patients with myelodysplastic syndrome/acute myeloid leukaemia or with
features suggestive of MDS/AML
\. History of another primary malignancy
\. History of leptomeningeal carcinomatosis
\. Patient with symptomatic central nervous system (CNS) metastases who are
neurologically unstable or require increasing doses of corticosteroids or
local CNS-directed therapy to control their CNS disease
\. History of active primary immunodeficiency
\. Immunocompromised patients
\. Active infection including tuberculosis, hepatitis B, hepatitis C, or
human immunodeficiency virus. Patients with a past or resolved HBV infection
are eligible. Patients positive for hepatitis C (HCV) antibody are eligible
only if polymerase chain reaction is negative for HCV RNA
\. Current or prior use of immunosuppressive medication within 14 days
before the first dose of durvalumab or tremelimumab
\. Receipt of live attenuated vaccine within 30 days prior to the first dose
of IP
\. Female patients who are pregnant or breastfeeding or male or female
patients of reproductive potential
\. Prior treatment with any PARP inhibitor including olaparib or
immunotherapy
\. Concomitant use of known strong or moderate cytochrome CYP3A inhibitors
and concomitant use of known strong or moderate CYP3A inducers
Exclusion criteria of STEP 2
Patients should not enter the study if any of the exclusion criteria from STEP
and the following criteria for STEP 2 are fulfilled
\. Patient with progression observed on CT scan performed after 6 weeks of
olaparib (STEP 1)

Exclusion Criteria

Exclusion criteria of STEP 1
Involvement in the planning and/or conduct of the study
Patient with mBRCA1 / 2 that are eligible for current marketing authorization for olaparib (ovarian cancer),and patient eligible for AstraZeneca registration clinical trials, particularly for the prostate cohort
Specific exclusion criteria each cohort
Metastatic breast cancer
Only for patient second line : patient with mBRCA1 / 2 that are eligible for
current marketing authorization for Olaparib (ovarian cancer) and patient
eligible for AstraZeneca registration clinical trials)
Metastatic lung cancer
Small cell cancer
oncogenic addiction : EGFR mutation or BRAF mutation or ALK rearrangement or ROS1 mutation Locally advanced or metastatic ovarian cancer
Patient with mBRCA1 / 2 that are eligible for current marketing authorization for Olaparib (ovarian cancer) and patient eligible for AstraZeneca registration clinical trials
Metastatic prostate cancer
Untreated or first line patients
Metastatic head and Neck cancer, Metastatic endometrial cancer, Metastatic
clear cell renal cancer, Metastatic pancreatic cancer & Metastatic urothelial
cancer
None
\. Participation in another clinical study with an investigational product
during within 2 months of first administration of Olaparib
\. Concurrent enrolment in another clinical study, unless it is an
observational (non-interventional) clinical study or during the follow-up
period of an interventional study
\. Receipt of the last dose of anticancer therapy 21 days prior to the first
dose of olaparib or 5 times its half-life, whichever is less
\. Any unresolved toxicity NCI CTCAE Grade 2 from previous anticancer therapy
with the exception of alopecia, ototoxicity, vitiligo, and the laboratory
Clear my responses

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