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
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
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.
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.
- 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) 1.1. 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 1.
- 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.
- It is unknown if niraparib or copanlisib are expressed in human breast milk. For this
reason, women must not breast-feed while taking the study medications.
- Absolute neutrophil count >= 1,500/mcL (within 7 days prior to entry/randomization).
- Hemoglobin >= 9 gm/dL (within 7 days prior to entry/randomization).
- Platelets >= 100,000/mcL (within 7 days prior to entry/randomization).
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (within 7 days
prior to entry/randomization) (< 2 x ULN for patients with Gilbert-Meulengracht
syndrome or for patients with cholestasis due to compressive adenopathies of the
- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN unless
the liver is involved with tumor, in that case, ALT/AST must be =< 5 x ULN (within 7
days prior to entry/randomization).
- Lipase =< 1.5 x ULN (within 7 days prior to entry/randomization).
- International normalized ratio (INR) =< 1.5 x ULN and partial thromboplastin time
(PTT) =< 1.5 x ULN (within 7 days prior to entry/randomization). Prothrombin time (PT)
can be used instead of INR if PTT =< 1.5 x ULN.
- Left ventricular ejection fraction (LVEF) >= 50% (within 7 days prior to
- Glomerular filtration rate (GFR) >= 50 mL/min/1.73 m^2 according to the Chronic Kidney
Disease Epidemiology Collaboration (CKD-EPI) equation. If not on target, the
evaluation may be repeated once after at least 24 hours either according to the
CKD-EPI equation or by 24 hour sampling. If the later result is within acceptable
range, it may be used to fulfill the inclusion criteria instead.
- Patients must be able to swallow and tolerate oral medications and not have
gastrointestinal illnesses that would preclude absorption of niraparib (e.g.
uncontrolled nausea, vomiting, or diarrhea; malabsorption syndrome; ulcerative
- Participants' life expectancy must be at least 3 months.
- Patients must be able to understand and willing to sign an informed consent.
- Patients must agree to not donate blood during the study or for 90 days after the last
dose of study treatment.
- For the expansion phase only: For the expansion phase, patients with recurrent
platinum sensitive disease must progress after treatment with a platinum doublet, and
patients with BRCA mutations must progress after maintenance therapy with PARP
- For the expansion phase only: For the expansion phase, patients must have measurable
disease accessible for biopsy.
- For the expansion phase only: Archival specimens from the time of primary or
- 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 2.
- Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3
months), myocardial infarction less than 6 months before start of test drug
Uncontrolled hypertension (despite optimal medical management).
- Arterial or venous thrombotic or embolic events such as cerebrovascular accident
(including transient ischemic attacks), deep vein thrombosis or pulmonary embolism
within 3 months before the start of study treatment.
- Non-healing wound, ulcer, or bone fracture.
- Glycosylated hemoglobin (HbA1c) > 8.5% at screening.
- Known history of human immunodeficiency virus (HIV) infection. All patients must be
screened for HIV up to 28 days prior to study drug start using a blood test for HIV
according to local regulations.
- Hepatitis B (HBV) or hepatitis C (HCV). All patients must be screened for HBV and HCV
up to 28 days prior to study drug start using the routine hepatitis virus laboratorial
panel. Patients positive for hepatitis B surface antigen (HBsAg) or hepatitis B virus
core antibody (HBcAb) will be eligible if they are negative for HBV-deoxyribonucleic
acid (DNA); patients positive for anti-HCV antibody will be eligible if they are
negative for HCV-ribonucleic acid (RNA).
- Patients with seizure disorder requiring medication.
- Proteinuria of >= Common Terminology Criteria for Adverse Events (CTCAE) (version 5.0)
grade 3 as assessed by a 24 hour total urine protein (estimated by urine protein :
creatinine ratio 3.5 on a random urine sample).
- History or concurrent condition of interstitial lung disease of any severity and/or
severely impaired lung function (as judged by the investigator).
- Concurrent diagnosis of pheochromocytoma.
- Unresolved toxicity higher than CTCAE (version 5.0) grade 1 attributed to any prior
therapy/procedure, excluding alopecia, peripheral neuropathy, and bone marrow
- Any illness or medical conditions that are unstable or could jeopardize the safety of
patients and their compliance in the study.
- As judged by the investigator, the patient is unsuitable to participate in the study
and the patient is unlikely to comply with study procedures, restrictions, and
- Active, clinically serious infections > CTCAE (version 5.0) grade 2.
- History of, or current autoimmune disease, including autoimmune thyroid disease.
- Cytomegalovirus (CMV) infection. Patients who are CMV polymerase chain reaction (PCR)
positive at baseline will not be eligible.
- Patients with evidence or history of bleeding diathesis. Any hemorrhage or bleeding
event >= CTCAE (version 5.0) grade 3 within 4 weeks prior to the start of the study
- Pregnant or breast feeding women. Women of childbearing potential must have a serum
pregnancy test performed a maximum of 7 days before start of treatment, and a negative
result must be documented before start of treatment.
- History of having received an allogenic bone marrow or organ transplant.
- Patient has any known history of myelodysplastic syndrome (MDS) or acute myeloid
- Patients has had radiation therapy encompassing > 20% of the bone marrow within 2
weeks or any radiation therapy within 1 week prior to day 1 of protocol therapy.
- Patient must not have received colony stimulating factors (e.g., granulocyte colony
stimulating factor, granulocyte macrophage colony stimulating factor, or recombinant
erythropoietin) within 4 weeks prior initiating protocol therapy.
- EXCLUDED PRIOR THERAPIES AND MEDICATIONS: - Myeloid growth factors less than 14 days
before start of treatment - Blood or platelet transfusion less than 7 days before
start of treatment - Ongoing systemic corticosteroid therapy at a daily dose higher
than 15 mg prednisone or equivalent. Previous corticosteroid therapy must be stopped
or reduced to the allowed dose 7 days before performing the screening computed
tomography (CT)/magnetic resonance imaging (MRI) and again prior to the first study
drug administration. If a patient is on chronic corticosteroid therapy,
corticosteroids should be de-escalated to the maximum allowed dose before the
screening. Patients may use topical or inhaled corticosteroids. - Anti-arrhythmic
therapy (beta blockers or digoxin are permitted) - Use of strong inhibitors and
inducers of CYP3A4 is prohibited from day -14 of cycle 1 until the end of study visit.
Copanlisib is primarily metabolized by CYP3A4. Therefore concomitant use of strong
inhibitors of CYP3A4(e.g., ketoconazole, itraconazole, clarithromycin, ritonavir,
indinavir, nelfinavir and saquinavir), and inducers of CYP3A (e.g. rifampin,
phenytoin, carbamazepine, phenobarbital, St. John's wort) are not permitted from day
-14 of cycle 1 until the end of study visit.
- For expansion phase only: Lack of accessible tumor for biopsy.