A Phase Ib Study of the Oral PARP Inhibitor Niraparib With the Intravenous PI3K Inhibitor Copanlisib for Recurrent Endometrial and Recurrent Ovarian, Primary Peritoneal, or Fallopian Tube Cancer
Overview
- Phase
- Phase 1
- Status
- Active, not recruiting
- Sponsor
- M.D. Anderson Cancer Center
- Enrollment
- 31
- Locations
- 1
- Primary Endpoint
- Maximum tolerated dose
Overview
Brief Summary
This phase Ib trial studies the best dose and side effects of niraparib and copanlisib in treating patients with endometrial, ovarian, primary peritoneal, or fallopian tube cancer that has come back. Niraparib and copanlisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Detailed Description
PRIMARY OBJECTIVES:
I. To determine the maximally tolerated dose (MTD) and recommended phase II dose (RP2D) of the combination of niraparib and copanlisib in patients with recurrent high-grade serous or BRCA mutant ovarian cancer or recurrent endometrial, fallopian tube, or primary peritoneal cancer.
SECONDARY OBJECTIVES:
I. To determine the tolerability of the RP2D of niraparib and copanlisib. II. To determine the safety and observed toxicities of the combination of niraparib and copanlisib in patients with recurrent endometrial, recurrent high-grade serous ovarian, or BRCA mutant ovarian cancer.
III. To estimate the activity of the drug combination at all dose levels in each patient cohort by objective response rate and proportion of patients surviving progression free (PFS) at 6 months.
IV. To determine response duration of the drug combination at all dose levels. V. To determine the pharmacokinetics (PK) of the combination to assess the presence of any drug interaction between the two co-administered agents.
EXPLORATORY OBJECTIVES:
I. To determine if response to therapy is associated with molecular profile of the tumor (including, but not limited to, molecular aberrations in the PI3K-AKT-mTOR pathway or defects in homologous recombination) before treatment.
II. To examine associations with early changes in functional proteomic biomarkers in tumor biopsies before and after treatment and tumor response in patients with recurrent endometrial, recurrent high-grade serous ovarian, or BRCA mutant ovarian cancer treated with the investigational agents.
OUTLINE: This is a dose-escalation study.
Patients receive niraparib orally (PO) daily on days 1-28 and copanlisib intravenously (IV) over 1 hour on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 and 90 days, then every 3 months for up to 5 years.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- Female
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Any histologically confirmed recurrent endometrial adenocarcinoma (except for carcinosarcoma), recurrent high-grade serous ovarian/primary peritoneal/fallopian tube carcinoma, or deleterious BRCA mutant recurrent ovarian/primary peritoneal/fallopian tube cancer for whom no curative option is available will be eligible. DOSE ESCALATION ONLY: For patients with ovarian cancer in the dose escalation cohort, only patients with recurrent, platinum resistant disease are eligible to enroll on study. Platinum resistance is defined as progression within 6 months from completion of platinum based therapy (the date should be calculated from the last administered dose of platinum therapy). In addition, patients in this cohort with a BRCA mutation must have also progressed after treatment with PARP inhibitor.
- •Patients may have unlimited prior chemotherapeutic regimens for management of recurrent endometrial or ovarian carcinoma. Patients who have received prior PARP inhibitors ARE allowed to participate. Patients who have received prior PI3K-pathway inhibitors ARE allowed to participate on the dose escalation phase ONLY. Patients may have progressed on prior PARP inhibitor and/or PI3K-pathway inhibitor but they may not have discontinued drug for toxicity.
- •With the exception of alopecia, peripheral neuropathy, and bone marrow parameters, any unresolved toxicities from prior chemotherapy should be no greater than Common Terminology Criteria for Adverse Events (CTCAE) (version 5.0) grade 1 at the time of starting study treatment.
- •Patients should have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.
- •If no measurable disease is present, patients should have assessable disease such as pleural effusion, ascites, with CA125 Gynecological Cancer Intergroup (GCIG) criteria.
- •Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or
- •The effects of niraparib and copanlisib on the developing human fetus are unknown. For this reason, women of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to taking study treatment. Female patients and their male partners must also agree to use effective contraception when sexually active. This applies since signing of the informed consent form and 6 months (for women of child bearing potential) after the last study drug administration. A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include but are not limited to hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy.
- •A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy. The investigator or a designated associate must advise the patient (WOCBP or men who have not undergone bilateral orchidectomy) how to achieve highly effective birth control method. Birth control should be used from the signing of the patient consent form and for 180 days following the last dose of niraparib. Acceptable methods of birth control include:
- •Two highly effective forms of contraception, defined as contraceptive methods with a failure rate of less than 1% per year when used consistently and correctly. Patients and their sexual partners who've undergone vasectomy or tubal occlusion must also use a male condom with spermicide.
- •Permanent sterilization, defined as hysterectomy, bilateral salpingectomy, bilateral oophorectomy, or bilateral orchidectomy; postmenopausal, defined as a female patient or sexual partner \> 45 years of age who has not menstruated for at least 12 consecutive months; total sexual abstinence.
Exclusion Criteria
- •Patients must not be simultaneously enrolled in an interventional clinical trial.
- •Patients with endometrial cancer may not have carcinosarcoma.
- •Patients who have recurrences that are amenable to potentially curative treatment with radiation therapy or surgery.
- •Patients who have a history of other malignancies except for basal cell or squamous cell skin cancer, in situ cervical cancer, unless they have been disease-free for at least three years. Patients may have dual primaries of ovarian and endometrial cancer, superficial bladder, or localized prostate cancer.
- •Patients who have had prior chemotherapy, biological therapy, radiation therapy, androgens, thalidomide, immunotherapy, other anticancer agents, and any investigational agents within 28 days of starting study treatment or autologous transplant less than 3 months before start of treatment unless evidence of progression since last treatment (not including palliative radiotherapy at focal sites) or within a time interval less than at least 5 half-lives of the investigational agent, whichever is longer, prior to the first scheduled day of dosing in this study.
- •Patients who have had major surgery within 3 weeks prior to entry into the study or be recovering from any effects of surgery. Patients may not have had minor surgery within 2 weeks or open biopsy less than 7 days prior to entry into the study.
- •Patients with known hypersensitivity to niraparib or copanlisib or any of their excipients. Patients may not have history of hypersensitivity to drugs with a similar chemical structure or class to niraparib or copanlisib.
- •Patients who have experienced intolerable adverse events per treating investigator due to other PARP inhibitors or PI3K-pathway inhibitors.
- •Patients with known history of cancer involvement of the central nervous system. A scan to confirm absence of brain metastasis is not required.
- •Congestive heart failure \> New York Heart Association (NYHA) class
Arms & Interventions
Treatment (niraparib, copanlisib)
Patients receive niraparib PO daily on days 1-28 and copanlisib IV on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Copanlisib (Drug)
Treatment (niraparib, copanlisib)
Patients receive niraparib PO daily on days 1-28 and copanlisib IV on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Niraparib (Drug)
Outcomes
Primary Outcomes
Maximum tolerated dose
Time Frame: Up to 4 weeks
Defined as the highest dose for which the posterior probability of toxicity is closest to 30%. Will employ the Bayesian optimal interval design. We will report the posterior probability of dose limiting toxicities (DLT) for each dose level and a 90% credible interval for the probability of DLT at each dose level.
Secondary Outcomes
No secondary outcomes reported