Olaparib and Tremelimumab in Treating BRCA1 or BRCA2 Mutation Carrier Patients with Recurrent Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Status: Active

Description

This phase I / II trial studies the side effects and best dose of tremelimumab when given together with olaparib in treating patients confirmed to carry a breast cancer 1 (BRCA1) or breast cancer 2 (BRCA2) germline mutation with ovarian, fallopian tube, or primary peritoneal cancer that has has come back. Tremelimumab is an antibody that may stimulate the immune system to fight cancer. Olaparib may block an enzyme that affects how cancer cells grow and divide. Giving tremelimumab and olaparib may work better in treating BRCA mutation carrier patients with ovarian, fallopian tube, or primary peritoneal cancer.

Eligibility Criteria

Inclusion Criteria

  • PHASE I: * Patients must have recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma for which standard curative measures do not exist and be confirmed to carry a germline mutation in the BRCA1 or BRCA2 gene * All patients must have measurable disease as defined by World Health Organization (WHO) criteria; measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded); each lesion must be > 1.0cm when measured by computed tomography (CT), magnetic resonance imaging (MRI), or caliper measurement by clinical exam; or > 2.0 cm when measured by chest x-ray; lymph nodes must be > 1.5 cm in short axis when measured by CT or MRI * Patients with both platinum-sensitive and platinum-resistant disease are eligible
  • PHASE I: * Patients must have received at least one course of platinum-based chemotherapy for the management of primary disease including carboplatin, cisplatin, or another platinum compound; this initial treatment may have included intraperitoneal therapy, consolidation, biologic/targeted agents, or extended therapy administered after surgical or non-surgical assessment * There are no restrictions on the total number of prior regimens patients may have received
  • PHASE I: Patients must have a Gynecologic Oncology Groups (GOG) performance status of 0, 1, or 2
  • PHASE I: Absolute neutrophil count (ANC) > 1,500/mcl
  • PHASE I: Platelets > 100,000/mcl
  • PHASE I: Hemoglobin > 10 g/dL
  • PHASE I: Creatinine < 1.5 x the institutional upper limit of normal (ULN)
  • PHASE I: Bilirubin < 1.5 x ULN
  • PHASE I: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x ULN
  • PHASE I: Alkaline phosphatase (ALP) < 2.5 x ULN
  • PHASE I: Women of child-bearing potential must have a negative pregnancy test prior to study entry and agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 180 days following completion of therapy; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately * A woman of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: ** Has not undergone a hysterectomy or bilateral oophorectomy; or ** Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months) * Contraception: Women of childbearing potential who are sexually active with a non-sterilized male partner must use at least one highly effective method of contraception from the time of screening and must agree to continue using such precautions for 180 days after the last dose of investigation products; the male partner of a female subject must also use male condom plus spermicide throughout this period; cessation of birth control after this point should be discussed with a responsible physician; not engaging in sexual activity is an acceptable practice; however, occasional abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception; female patients should refrain from breastfeeding and egg cell donation throughout this period
  • PHASE I: Ability to understand and the willingness to sign a written informed consent document; patients must sign an approved informed consent and authorization permitting release of personal health information
  • PHASE I: Patients must meet pre-entry requirements as specified
  • PHASE II: * Patients must have recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma and be confirmed to carry a germline mutation in BRCA1 or BRCA2 * All patients must have measurable disease as defined by WHO criteria; measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded); each lesion must be > 1.0 cm when measured by CT, MRI, or caliper measurement by clinical exam; or > 2.0 cm when measured by chest x-ray; lymph nodes must be > 1.5 cm in short axis when measured by CT or MRI * Patients with both platinum-sensitive and platinum-resistant disease are eligible
  • PHASE II: * Patients must have received at least one course of platinum-based chemotherapy for the management of primary disease including carboplatin, cisplatin, or another organoplatinum compound; this initial treatment may have included intraperitoneal therapy, consolidation, biologic/targeted agents, or extended therapy administered after surgical or non-surgical assessment * There are no restrictions on the total number of prior regimens patients may have received
  • PHASE II: Patients must have a GOG performance status of 0, 1, or 2
  • PHASE II: Absolute neutrophil count (ANC) > 1,500/mcl
  • PHASE II: Platelets > 100,000/mcl
  • PHASE II: Hemoglobin > 10 g/dL
  • PHASE II: Creatinine < 1.5 x the institutional ULN
  • PHASE II: Bilirubin < 1.5 x ULN
  • PHASE II: AST and ALT < 3 x ULN
  • PHASE II: ALP < 2.5 x ULN
  • PHASE II: Women of child-bearing potential must have a negative pregnancy test prior to study enrollment and agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 180 days following completion of therapy; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately * A woman of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria ** Has not undergone a hysterectomy or bilateral oophorectomy; or ** Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months) * Contraception: Women of childbearing potential who are sexually active with a non-sterilized male partner must use at least one highly effective method of contraception from the time of screening and must agree to continue using such precautions for 180 days after the last dose of investigational products; the male partner of a female subject must also use male condom plus spermicide throughout this period; cessation of birth control after this point should be discussed with a responsible physician; not engaging in sexual activity is an acceptable practice; however, occasional abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception; female patients should refrain from breastfeeding and egg cell donation throughout this period
  • PHASE II: Ability to understand and the willingness to sign a written informed consent document; patients must sign an approved informed consent and authorization permitting release of personal health information
  • PHASE II: Patients must meet pre-entry requirements as specified

Exclusion Criteria

  • PHASE I: Recovery from effects of recent surgery, radiotherapy, or chemotherapy must be demonstrated
  • PHASE I: Patients should be free of active infection requiring antibiotic therapy (except for uncomplicated urinary tract infections)
  • PHASE I: Hormonal therapy directed at treatment for the cancer must be discontinued at least one week prior to enrollment; hormone replacement therapy for symptom management is permitted
  • PHASE I: Any other therapy directed at treating the cancer including chemotherapy, biologic/targeted agents, and immunologic agents, must be discontinued at least three weeks prior to enrollment
  • PHASE I: Any prior radiation therapy must be discontinued at least four weeks prior to enrollment
  • PHASE I: A history of autoimmune disorders * Patients with autoimmune disease other than vitiligo (e.g., psoriasis, extensive atopic dermatitis, asthma, irritable bowel disorder [IBD], muscular sclerosis [M.S.], uveitis, vasculitis), chronic inflammatory condition, or any condition requiring concurrent use of any systemic immunosuppressants or steroids for any reason are excluded from the study; any patient with an allo-transplant of any kind would be excluded as well, including xenograft heart valve; mild, intermittent asthma requiring only occasional beta-agonist inhaler use or mild localized eczema will not be excluded * Chronic use of immune-suppressive drugs (i.e., systemic corticosteroids used in the management of cancer or non-cancer related illnesses, e.g., chronic obstructive pulmonary disease [COPD]) * Known human immunodeficiency virus [HIV]-positive patients and those with other acquired/inherited immunodeficiencies are ineligible due the possibility of affecting the response to tremelimumab, and the higher risk of active opportunistic infections
  • PHASE I: History of allergic reactions attributed to compounds of similar chemical or biologic composition to olaparib or tremelimumab, or other agents used in study
  • PHASE I: Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • PHASE I: Concomitant use of known potent cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inhibitors
  • PHASE I: Persistent toxicities (> Common Terminology Criteria for Adverse Event [CTCAE] grade 2) caused by prior cancer therapy, excluding alopecia
  • PHASE I: Patients must not be pregnant or nursing as the potential of this regimen to harm nursing infants has not been evaluated
  • PHASE I: Patients who are receiving any other investigational agent
  • PHASE I: Resting electrocardiogram (ECG) with corrected QT QTc) > 470msec on two or more time points within a 24h period, or a family history of long QT syndrome
  • PHASE I: Patients who have previously received anti-cytotoxic T-lymphocyte antigen (CTLA)-4 antibody therapy
  • PHASE I: No blood transfusions 28 days prior to study entry
  • PHASE I: No features suggestive of myelodysplastic syndrome/ acute myeloid leukemia
  • PHASE II: * Patients without measurable disease by imaging * Patients with persistent platinum-refractory disease after primary therapy
  • PHASE II: Recovery from effects of recent surgery, radiotherapy, or chemotherapy must be demonstrated
  • PHASE II: Patients should be free of active infection requiring antibiotic therapy (except for uncomplicated urinary tract infections)
  • PHASE II: Hormonal therapy directed at treatment for the cancer must be discontinued at least one week prior to enrollment; hormone replacement therapy for symptom management is permitted
  • PHASE II: Any other therapy directed at treating the cancer including chemotherapy, biologic/targeted agents, and immunologic agents, must be discontinued at least three weeks prior to enrollment
  • PHASE II: Any prior radiation therapy must be discontinued at least four weeks prior to enrollment
  • PHASE II: Resting ECG with QTc > 470msec on two or more time points within a 24h period, or a family history of long QT syndrome
  • PHASE II: Concomitant use of known potent CYP3A4 inhibitors
  • PHASE II: Persistent toxicities (> Common Terminology Criteria for Adverse Event [CTCAE] grade 2) caused by prior cancer therapy, excluding alopecia
  • PHASE II: A history of autoimmune disorders * Patients with autoimmune disease other than vitiligo (e.g., psoriasis, extensive atopic dermatitis, asthma, IBD, M.S., uveitis, vasculitis), chronic inflammatory condition, or any condition requiring concurrent use of any systemic immunosuppressants or steroids for any reason are excluded from the study; any patient with an allo-transplant of any kind would be excluded as well, including xenograft heart valve; mild, intermittent asthma requiring only occasional beta-agonist inhaler use or mild localized eczema will not be excluded * Chronic use of immune-suppressive drugs (i.e., systemic corticosteroids used in the management of cancer or non-cancer related illnesses, e.g., COPD) * Known HIV-positive patients and those with other acquired/inherited immunodeficiencies are ineligible due the possibility of affecting the response to tremelimumab, and the higher risk of active opportunistic infections
  • PHASE II: Patients who are receiving any other investigational agent
  • PHASE II: Patients who have previously received anti-CTLA-4 antibody therapy
  • PHASE II: History of allergic reactions attributed to compounds of similar chemical or biologic composition to olaparib or tremelimumab, or other agents used in study
  • PHASE II: Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • PHASE II: Patients must not be pregnant or nursing as the potential of this regimen to harm nursing infants has not been evaluated
  • PHASE II: No blood transfusions 28 days prior to study entry
  • PHASE II: No features suggestive of myelodysplastic syndrome/ acute myeloid leukemia

Locations & Contacts

New Mexico

Albuquerque
New Mexico Cancer Care Alliance
Status: Active
Contact: Sarah F. Adams
Phone: 505-925-0461
Email: SAdams@salud.umn.edu
University of New Mexico Cancer Center
Status: Active
Contact: Sarah F. Adams
Phone: 505-925-0461
Email: SAdams@salud.unm.edu

Ohio

Columbus
Ohio State University Comprehensive Cancer Center
Status: Active
Contact: David M. O'Malley
Phone: 614-293-3145

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To define the safety profile of tremelimumab and olaparib in women with BRCA1 or BRCA2 mutation-associated ovarian, tubal, or primary peritoneal cancer who are refractory to standard therapy. (Phase I)

II. To determine the preliminary efficacy of the combination of tremelimumab and olaparib as measured by objective response (partial plus complete remission) according to the new immune-related response criteria in solid tumors (irRC). (Phase II)

SECONDARY OBJECTIVES:

I. To determine progression free survival (PFS) according to the new irRC in solid tumors. (Phase II)

II. To determine the adverse event profile and tolerability of the combination of tremelimumab and olaparib in patients with BRCA1 or BRCA2 mutation-associated ovarian cancer. (Phase II)

TERTIARY OBJECTIVES:

I. To evaluate immunologic correlates of response to combination therapy (absolute lymphocyte count, myeloid derived suppressor cell numbers, T cell subsets, T cell function and specificity) in both peripheral blood and tumor (when possible).

II. To identify biomarkers of response to combined targeted and immune therapy through genomic analysis and cytokine profiling of peripheral blood samples.

III. To explore whether resistance mechanisms to poly(ADP-ribose) polymerase (PARP)-inhibitors can be overcome with the addition of immune checkpoint blockade.

IV. The exploratory analyses may not be reported in the clinical study report (CSR), if not, they will be reported separately.

OUTLINE: This is a dose de-escalation study of tremelimumab.

Patients receive olaparib orally (PO) twice daily (BID) on days 1-28 and tremelimumab intravenously (IV) once every 4 weeks for 6 doses and then once every 12 weeks. Treatment repeats every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.

Trial Phase & Type

Trial Phase

Phase I/II

Trial Type

Treatment

Lead Organization

Lead Organization
University of New Mexico Cancer Center

Principal Investigator
Sarah F. Adams

Trial IDs

Primary ID INST 1419
Secondary IDs NCI-2016-00434, UNM 1419
Clinicaltrials.gov ID NCT02571725