Immunotherapy
Conditions
Keywords
immunotherapy, olaparib, durvalumab, tremelimumab, genes mutation
Brief 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.
Detailed 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)-γ and tumor necrosis factor-α 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.
Interventions
DRUGolaparib, durvalumab, tremelimumab
STEP 1: Olaparib 300 mg BID during 8 weeks. Olaparib tablets should be taken at the same time each day, approximately 12 hours apart with one glass of water. The tablets should be swallowed whole and not chewed, crushed, dissolved or divided. Olaparib tablets can be taken with or without food STEP 2: Olaparib 300 mg during 4 months as per same requirement as below. Durvalumab 1500 mg plus tremelimumab 75 mg via IV infusion Q4W, starting on Week 0, for up to a maximum of 4 doses followed by durvalumab monotherapy 1500 mg via IV infusion Q4W, starting 4 weeks after the last infusion of the combination and in response or stable after prior molecular target therapy by olaparib based on molecular sequencing.
Sponsors
AstraZeneca
Centre Georges Francois Leclerc
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Inclusion Criteria from STEP 1: 1. Capable of giving signed informed consent 2. Exome sequencing of tumor and constitutive DNA should have been already performed 3. Patients must be diagnosed with a solid malignancy with the following cancer histologically confirmed with specified inclusion for each cohort: Metastatic breast cancer: • In second line • third line and after Metastatic lung cancer: * Non-small cell lung cancer * Must have progressed after at least a first line with platinum based therapy Metastatic head and Neck cancer • Must have progressed after at least a first line with platinum based therapy Metastatic endometrial cancer • Progression after 1 prior systemic, platinum-based chemotherapy regimen for EC. Participants may have received up to 1 additional line of platinum-based chemotherapy if given in the neoadjuvant or adjuvant treatment setting. There is no restriction regarding prior hormonal therapy Metastatic clear cell renal cancer • Must have progressed after at least a line with anti-angiogenic agent. Metastatic pancreatic cancer • Must have progressed after at least a line with FOLFIRINOX regimen and/or Gemcitabin based chemotherapy Locally advanced or metastatic ovarian cancer • Must have received at least one and no more than two lines of prior platinum-containing therapy and progressed after the most recent platinum therapy in a platinum-sensitive timeframe (more than 6 months from the last dose of platinum before randomization) Metastatic urothelial cancer • From the second line and regardless previous treatment (except immunotherapy) Metastatic prostate cancer * Documented evidence of metastatic castration resistant prostate cancer (mCRPC) * Ongoing therapy with LHRH analog or bilateral orchiectomy * Must have progressed on prior new hormonal agent (enzalutamine or abiraterone) and taxane chemotherapy 4. Presence of mutation in homologous repair gene 5. Age \>18 years 6. Performance status ECOG of 0 or 1. 7. Life expectancy ≥ 6 months. 8. At least one lesion measurable as defined by standard imaging criteria for the patient's tumor type (RECIST v1.1) 9. Body weight \>30 kg. 10. 10\. Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment 11. Postmenopausal or evidence of non-childbearing status for women of childbearing potential 12. Male patients must use a condom during treatment of STEP1 (olaparib) and STEP2 (durvalumab and tremelimumab) and for 180 days after the last dose when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male patients should also use a highly effective form of contraception if they are of childbearing potential 13. Patient is willing and able to comply with the protocol for the duration of the study. 14. For all oral medications patients must be able to comfortably swallow capsules; Inclusion criteria STEP 2 16\. CT Scan evaluation after 6 weeks of olaparib should present response or stable disease as defined by RECIST v1.1 criteria.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety Assessments: progression free survival | 6 months after the initiation of immunotherapy for all cohorts excepted for ovarian cohort where PFS will be evaluated at 12 months. | progression free survival |
Countries
France
Outcome results
None listed