Olaparib, Durvalumab, and Tremelimumab in Treating Patients With Recurrent or Refractory Ovarian, Fallopian Tube or Primary Peritoneal Cancer With BRCA1 or BRCA2 Mutation

NCT02953457 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: I 288216NCI-2016-01598
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 2

Brief Summary

This phase I/II trial studies the side effects and best dose of olaparib when give together with durvalumab and tremelimumab and to see how well they work in treating patients with ovarian, fallopian tube, or primary peritoneal cancer with BRCA1 or BRCA2 genetic mutation that has come back or has not responded to treatment. Drugs, such as olaparib, may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and kill tumors cells with BRCA1 or BRCA2 mutation. Monoclonal antibodies, such as durvalumab and tremelimumab, may help stimulate the immune system in different ways to attack and stop tumor cells from growing. Giving olaparib with durvalumab and tremelimumab may work better in treating patients with ovarian, fallopian tube, or primary peritoneal cancer.

Conditions

BRCA1 Gene Mutation; BRCA2 Gene Mutation; Ovarian Serous Adenocarcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma

Outcome Measures

Primary Outcomes (3)

• Incidence of Dose-limiting Toxicities (DLTs) Defined as the Rate of Drug-related Grade 3-5 Adverse Events Assessed Using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 (Phase I)

  The maximum tolerated dose is defined as the highest dose studied, for which the observed incidence of DLT is less than 33%. Number of Participants with Dose-limiting Toxicities (DLTs) in Phase I and Phase II will be reported.

  Up to 8 weeks

• 3 Month Progression Free Survival (PFS) in the All Eligible Patients by Group/Arm

  Progression free survival (PFS) rate will be assessed at 3 months in the platinum resistant group using Kaplan-Meier methods. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

  At 3 months

• 6 Month Progression Free Survival (PFS) in the Platinum Sensitive Group (Phase II)

  6-month progression-free survival rate is the probability of patients remaining alive and progression-free at 6 months from study entry estimated using Kaplan-Meier methods. Per RECIST 1.0 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesion

  At 6 months

Secondary Outcomes (2)

• Anti-tumor Immune Response of the Treatment Combination Assessed in Tumor Biopsy

  At 12 weeks

• Overall Survival (OS)

  35 months

Study Arms (1)

Treatment (olaparib, tremelimumab, durvalumab)

EXPERIMENTAL

Patients receive olaparib PO BID, and tremelimumab IV over 1 hour and durvalumab IV over 1 hour on day 1. Treatment with olaparib continues for up to 12 months in the absence of disease progression or unacceptable toxicity. Treatment with tremelimumab repeats every 4 weeks for up to 4 courses and treatment with durvalumab repeats every 4 weeks for up to 13 courses in the absence of disease progression or unacceptable toxicity.

Biological: Durvalumab; Other: Laboratory Biomarker Analysis; Drug: Olaparib; Biological: Tremelimumab

Interventions

Durvalumab BIOLOGICAL

Given IV

Also known as: Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer, MEDI-4736, MEDI4736

Treatment (olaparib, tremelimumab, durvalumab)

Laboratory Biomarker Analysis OTHER

Correlative studies

Treatment (olaparib, tremelimumab, durvalumab)

Olaparib DRUG

Given PO

Also known as: AZD2281, KU-0059436, Lynparza, PARP Inhibitor AZD2281

Treatment (olaparib, tremelimumab, durvalumab)

Tremelimumab BIOLOGICAL

Given IV

Also known as: Anti-CTLA4 Human Monoclonal Antibody CP-675,206, CP-675, CP-675,206, CP-675206, Ticilimumab

Treatment (olaparib, tremelimumab, durvalumab)

Eligibility Criteria

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

You may qualify if:

• Patients must have platinum-sensitive or platinum-resistant recurrent or persistent or refractory ovarian, fallopian tube, or primary peritoneal carcinoma AND have one or more of the following characteristics documented on a validated platform (documented genetic test report is required). Historic report is permitted.
• A germline BRCA1 or BRCA2 deleterious alteration.
• A somatic mutation in BRCA1 or BRCA2 detected in a tumor sample or on circulating tumor DNA
• Carry a known or likely loss of function alteration in one or more of the homologous recombination or mismatch repair pathways genes
• Demonstrate a genomic phenotype of HR deficiency as measured by a LOH-high score.
• Recurrent ovarian cancer is defined as recurrence of disease in a patient who achieved initial complete response to primary therapy
• Persistent ovarian cancer is defined as having residual disease in the form of elevated tumor markers or microscopic or clinically evident disease in a patient who has completed and apparently responded to initial chemotherapy
• Refractory ovarian cancer is defined as patients who have failed to achieve at least a partial response to therapy including patients with either stable disease or disease progression during primary therapy
• Platinum-sensitive is defined as achievement of documented response to initial platinum-based treatment and has been off treatment for an extended period of time (more than 6 months)
• Platinum-resistant is defined as relapse within 6 months of last platinum-based chemotherapy or progression while on platinum-based therapy
• All patients must have measurable disease as defined by immune-related Response Evaluation Criteria in Solid Tumors (irRECIST); measurable disease is defined as 10 mm in the longest diameter by computed tomography (CT) or magnetic resonance imaging (MRI) scan (or no less than double the slice thickness) for non- nodal lesions and \>= 15 mm in short axis for nodal lesions, 20 mm by chest X-ray, a lymph node must be \>= 15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm)
• Must have archival tissue available for PD-L1 assessment
• Patients should be free of active infection requiring antibiotics (with the exception of uncomplicated urinary tract infection \[UTI\])
• Patients who have the following risk factors are considered to be at increased risk for cardiac toxicities and may be enrolled only with increased monitoring: i) prior treatment with anthracyclines; ii) prior treatment with trastuzumab; iii) a New York Heart Association classification of II controlled with treatment; iv) prior central thoracic radiation therapy (RT), including RT to the heart
• Any hormonal therapy being taken as a treatment for cancer must be discontinued at least one week prior to registration; continuation of hormone replacement therapy e.g. thyroid hormone replacement therapy is permitted

You may not qualify if:

• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site); previous enrollment in the present study
• Participation in another clinical study with an investigational product during the last 4 weeks (prior use of bevacizumab in the upfront setting is allowed)
• History of discontinuation of any previous treatment with PARP inhibitors, including olaparib, or a PD-1 or PD-L1 inhibitor, including durvalumab or anti-CTLA4 antibody, including tremelimumab due to toxicity.
• Patients with myelodysplastic syndrome/acute myeloid leukemia
• History and/or confirmed interstitial lung disease (ILD)/pneumonitis, extensive bilateral lung disease on high-resolution computed tomography (HRCT) scan
• Concomitant use of a strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, ketoconazole, voriconazole, nefazodone, posaconazole, ritonavir, lopinavir/ritonavir, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) and moderate CYP3A inhibitors (e.g., amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, erythromycin, fluconazole. Fosamprenavir, imatinib, verapamil)
• Concomitant use of strong CYP3A inducers (e.g., phenytoin, rifampicin, carbamazepine, St. John's wort) and moderate CYP3A inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin)
• History of another primary malignancy except for:
• Malignancy treated with curative intent and with no known active disease \>= 5 years before the first dose of study drug and of low potential risk for recurrence
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease (e.g. basal cell or squamous cell carcinoma of the skin)
• Adequately treated carcinoma in situ without evidence of disease (e.g., breast and cervical cancer in situ)
• Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, radiotherapy or other investigational agent) =\< 21 days prior to the first dose of study drug and within 6 weeks for nitrosourea or mitomycin C)
• Mean QT interval corrected for heart rate (QTcF) \>= 470 ms calculated from 3 electrocardiograms (ECGs) using Fridericia's correction
• Patients with history of myocardial infarction within 6 months
• Current or prior use of immunosuppressive medication within 28 days before the first dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid

Sponsors & Collaborators

• Roswell Park Cancer Institute: lead
• AstraZeneca: collaborator

Study Sites (2)

Roswell Park Cancer Institute

Buffalo, New York, 14263, United States

Location

The Feinstein Institute for Medical Research/Lennox Hill Hospital

New York, New York, 10075, United States

Location

MeSH Terms

Conditions

Fallopian Tube Neoplasms; Ovarian Neoplasms

Interventions

durvalumab; Immunoglobulin G; Disulfides; olaparib; tremelimumab

Condition Hierarchy (Ancestors)

Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Fallopian Tube Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Endocrine Gland Neoplasms; Ovarian Diseases; Endocrine System Diseases; Gonadal Disorders

Intervention Hierarchy (Ancestors)

Immunoglobulin Isotypes; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Sulfides; Anions; Ions; Electrolytes; Inorganic Chemicals; Hydrogen Sulfide; Sulfur Compounds; Organic Chemicals

Results Point of Contact

• Title: Katy Wang
• Organization: Roswell Park Comprehensive Cancer Center

Chong.Wang@Roswellpark.org

716-845-1300

Study Officials

• Emese Zsiros

  Roswell Park Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

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: November 1, 2016
• First Posted: November 2, 2016
• Study Start: June 29, 2017
• Primary Completion: September 15, 2021
• Study Completion: August 15, 2024
• Last Updated: November 19, 2024
• Results First Posted: October 5, 2022

Record last verified: 2024-10

Locations

US (2)