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BRCA1 Gene MutationPhase 2NCT02953457

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

A Phase 2 study testing Durvalumab, Laboratory Biomarker Analysis and Olaparib in people with BRCA1 Gene Mutation and BRCA2 Gene Mutation, run by Roswell Park Cancer Institute at 2 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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… Read more about this study

Who is it for?
Ages 18 years and older, women only
What is being tested?
Durvalumab, Laboratory Biomarker Analysis and Olaparib
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
40 participants
Where
2 sitesUnited States
Study dates
29 Jun 2017to 15 Aug 2024
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • Women only
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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
  • Able to tolerate oral medications and no GI illnesses that would preclude absorption of olaparib
  • Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
  • Life expectancy of > 6 months
  • Hemoglobin >= 10 g/dL (no blood transfusion in the 28 days prior to entry [olaparib guidelines])
  • White blood cell count (WBC) > 3 x 10^9/L
  • Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (>=1500 per mm^3)
  • Platelet count >= 100 x 10^9/L (>= 100,000 per mm^3)
  • Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN); this will not apply to subjects with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be =< 5 x ULN
  • Creatinine =< 1.5 x ULN, serum creatinine clearance (CL) > 51 ml/min (by the Cockcroft- Gault equation)
  • Female subjects must either be of non-reproductive potential (i.e., post-menopausal by history: >= 60 years old and no menses for >=1 year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum pregnancy test within 28 days of study treatment, confirmed prior to treatment on day 1
  • Participants of child-bearing potential must agree to use two highly effective and acceptable forms of contraception from screening, throughout their participation in the study and for 180 days after the last dose of durvalumab + tremelimumab combination therapy or 90 days after last dose of durvalumab or olaparib, whichever is the longer time period (e.g., hormonal or barrier method of birth control); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
  • Participant or legal representative must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure
  • Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up

Who cannot join

  • 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)
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  • 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
  • Any unresolved toxicity (Common Terminology Criteria for Adverse Events [CTCAE] grade >= 2) from previous anti-cancer therapy; subjects with irreversible toxicity that is not reasonably expected to be exacerbated by the investigational product may be included (e.g., hearing loss, peripherally neuropathy)
  • Any prior grade >= 3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE > grade 1
  • Active or prior documented autoimmune disease within the past 2 years; NOTE: Subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded
  • Active or prior documented inflammatory bowel disease (e.g., Crohn?s disease, ulcerative colitis)
  • Patients with thyroid dysfunction if not adequately controlled
  • History of primary immunodeficiency
  • History of allogeneic organ transplant
  • History of hypersensitivity to durvalumab, tremelimumab, olaparib or, any excipient
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have evidence of, or test positive for, acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent
  • Known history of previous clinical diagnosis of tuberculosis
  • History of leptomeningeal carcinomatosis
  • Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab (e.g. live attenuated influenza vaccine [LAIV], measles/mumps/rubella vaccine [MMR], variola virus vaccine [VAR], zoster, yellow fever, etc.)
  • Female subjects who are pregnant, breast-feeding, or of reproductive potential who are not employing an effective method of birth control from screening to 180 days after the last dose of durvalumab + tremelimumab + olaparib combination therapy or 90 days after the last dose of durvalumab and olaparib therapy, whichever is the longer time period
  • Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results or, is an unsuitable candidate to receive study drug (e.g. inability to tolerate oral medications which would preclude absorption of olaparib)
  • Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroids
  • Subjects with uncontrolled seizures
  • Dependency on IV hydration or total parenteral nutrition (TPN)

Trial locations and contacts

2 sites in 1 country.

United States2 sites

  • Roswell Park Cancer Institute

    Buffalo, New York, 14263

  • The Feinstein Institute for Medical Research/Lennox Hill Hospital

    New York, New York, 10075

Other trials in United States

About this study

Official title: A Phase I/II Evaluation of Olaparib in Combination With Durvalumab (Medi4736) and Tremelimumab in the Treatment of Recurrent Platinum Sensitive or Resistant or Refractory Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer in Patients Who Carry a BRCA1 or BRCA2 Mutation

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.

Read the detailed description

PRIMARY OBJECTIVES:

  1. To assess the safety and toxicity of the combination of PARP inhibitor olaparib with anti-PD-L1 antibody durvalumab and anti-CTLA4 antibody tremelimumab. (Phase I) II. To assess the impact of the combination of olaparib with durvalumab and tremelimumab on progression free survival (PFS) rates. (Phase II)

SECONDARY OBJECTIVES:

  1. To assess the impact of the combination of olaparib with durvalumab and tremelimumab on anti-tumor immune responses in patients with recurrent platinum sensitive or resistant or refractory epithelial ovarian, fallopian tube, or primary peritoneal cancer who carry a germline and/or somatic BRCA1 or BRCA2 mutation and/or a homologous recombination deficiency (HRD).

II. To assess the impact of the combination of olaparib with durvalumab and tremelimumab on PFS and overall survival (OS) in patients with recurrent platinum sensitive or resistant or refractory epithelial ovarian, fallopian tube, or primary peritoneal cancer who carry a germline and/or somatic BRCA1 or BRCA2 mutation and/or a HRD.

OUTLINE: This is a phase I, dose-escalation study of olaparib followed by a phase II study.

Patients receive olaparib orally (PO) twice daily (BID), and tremelimumab intravenously (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.

After completion of study treatment, patients are followed up at 30 and 90 days, and every 2 months thereafter.

Being tested
Durvalumab, Laboratory Biomarker Analysis, Olaparib, Tremelimumab
Medical subject headings
Fallopian Tube Neoplasms, Ovarian Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • DurvalumabBiological

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

    Given IV

  • Laboratory Biomarker AnalysisOther

    Correlative studies

  • OlaparibDrug

    Also called AZD2281, KU-0059436, Lynparza, PARP Inhibitor AZD2281

    Given PO

  • TremelimumabBiological

    Also called Anti-CTLA4 Human Monoclonal Antibody CP-675,206, CP-675, CP-675,206, CP-675206

    Given IV

Study groups in NCT02953457
Study groupRoleWhat they receive
Treatment (olaparib, tremelimumab, durvalumab)ExperimentalPatients 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.
Receives: Biological: Durvalumab; Other: Laboratory Biomarker Analysis; Drug: Olaparib; Biological: Tremelimumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Up to 8 weeks

  2. 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.

    Measured: At 3 months

  3. 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

    Measured: At 6 months

Secondary outcomes (2)

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

    Tumor biopsy samples will be examined to evaluate the correlation between clinical activity and the expression level of PD-L1 and tumor-infiltrating lymphocytes changes in biopsies pre and post treatment.

    Measured: At 12 weeks

  2. Overall Survival (OS)

    OS will be summarized and analyzed descriptively via summary frequencies and Kaplan-Meier estimators.

    Measured: 35 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted2 Nov 2016 (estimated)
  2. Study start29 Jun 2017
  3. Primary completion15 Sep 2021
  4. Study completion15 Aug 2024

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
40 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02953457
Sponsor's protocol ID
I 288216
Other IDs
NCI-2016-01598, I 288216
Status last verified
Oct 2024
First submitted
1 Nov 2016
Last updated
19 Nov 2024
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Durvalumab, Laboratory Biomarker Analysis and Olaparib in people with BRCA1 Gene Mutation and BRCA2 Gene Mutation, run by Roswell Park Cancer Institute at 2 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 29 inclusion and 32 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 19 Nov 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 5 Oct 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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) (time frame: Up to 8 weeks). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02953457.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Nov 2024.

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