| Eligibility |
Inclusion Criteria:
1. Histologically confirmed ER+ and/or PR+ advanced or metastatic solid cancer including
ovarian cancer (cohort 1), endometrial cancer (cohort 2), or breast cancer (cohort 3)
(Figure 1). ER and/or PR positivity is defined as >10% immunohistochemical staining of
any intensity. Cohort 3 will be enriched to include at least 7 patients naive to any
PI3Ki in Stage 1 and also in Stage 2.
2. Presence of one or more PI3K and/or PTEN alterations in tumor tissue. Genetic
alterations will include PIK3CA gain of function mutations, PIK3R1 loss of function
mutations, PTEN loss of function mutations, and PTEN deletions.
3. Measurable disease per the RECIST 1.1.
4. The patient (or legally acceptable representative, if applicable) provides written
informed consent for the study.
5. Female or male =18 years of age on the day of informed consent signing.
6. Patients have no available standard therapy known to prolong survival. For cohort 3
only, prior treatment with aPI3Ki or everolimus is not required and patients with or
without prior PI3Ki or everolimus will be qualified for enrollment
7. Adequate archived tumor tissue for the analysis for PI3K and PTEN alterations if
available.
8. Eastern Cooperative Oncology Group (ECOG) performance status of .2.
9. Adequate organ and marrow function as defined below:
1. Hemoglobin = 9.0 g/dL
2. Absolute neutrophil count =1.5 x 10^9/L
3. Platelet count = 100 x 10^9/L
4. Total bilirubin (TB) =1.5 × institutional upper limit of normal (ULN); Patients
with known Gilbert's disease who have TB =3 × ULN may be enrolled)
5. Aspartate transaminase (AST)/ alanine transaminase (ALT) =3 × ULN. If patient has
liver metastases, AST and ALT =5.0 × ULN.
6. Creatinine =1.5 x ULN
7. International normalized ratio =1.5.
10. Fasting blood glucose =140 mg/dL and hemoglobin A1c =8.5% (both criteria have to be
met).
11. Cardiac ejection fraction =45%.
12. Women of childbearing potential must have a negative serum or urine pregnancy test
(minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin
[HCG]) within 14 days prior to the initiation of treatment and/or postmenopausal women
must be amenorrheic for at least 12 months to be considered of non-childbearing
potential. Women of childbearing potential (WOCBP) must agree and commit to the use of
2 highly effective methods of birth control throughout the duration of the study until
at least 150 days following the last dose of study drug. Acceptable methods are
defined as those that result, alone or in combination, in a low failure rate (i.e.,
less than 1% per year) when used consistently and correctly, such as surgical
sterilization, an intrauterine device, or hormonal contraception in combination with a
barrier method. Women using systemically acting hormonal contraceptives should add a
barrier method. In certain countries (if permitted by law), WOCBP may agree to abide
by heterosexual sexual abstinence during the time of participation in this study.
13. Male patients and their female partners of childbearing potential must agree and
commit to use a barrier contraception (eg, condom with spermicidal
foam/gel/film/cream/suppository) throughout the duration of the study until at least
90 days following the last dose of study drug, in addition to their female partners
using either an intrauterine device or hormonal contraception and continuing until at
least 90 days following the last dose of study drug. This criterion may be waived for
male patients who have had a vasectomy > 6 months before signing the ICF.
14. Willing and able to comply with the protocol for the duration of the study including
undergoing treatment and scheduled visits and examinations.
Exclusion Criteria:
1. The patient has central nervous system (CNS) involvement. If the patient fulfills the
following 3 criteria, she/he is eligible for the study:
1. Completed prior therapy (including radiation and/or surgery) for CNS metastases,
and
2. CNS tumor is radiologically stable for = 28 days prior to study start, and
3. The patient is not receiving steroids and enzyme-inducing antiepileptic
medications for brain metastases.
2. Patients with HER2 positive breast cancer.
3. Patients must be =4 weeks or at least 5 half-lives beyond treatment with any
chemotherapy or other investigational therapy including hormonal, biological, or
targeted agents at the time of treatment initiation.
- NOTE: If the patient received major surgery, she/he must have recovered adequately
from the toxicity and/or complications from the intervention prior to starting the
study treatment.
4. Prior treatment with fulvestrant or any PI3Ki for cohorts 1 and 2.
5. Known hypersensitivity to copanlisib or fulvestrant, or to any of the excipients of
copanlisib or fulvestrant.
6. Concomitant use of strong cytochrome P450 (CYP)3A4 inducers (e.g., rifampicin,
phenytoin, carbamazepine, phenobarbital, St. John's wort) or inhibitors (e.g.,
ritonavir, saquinavir, nelfinavir, boceprevir, telaprevir, ketoconazole, omeprazole).
Use of strong inhibitors and/or inducers of CYP3A4 is not permitted from Day -14 of
Cycle 1 until the start of the study intervention.
7. The patient is currently receiving warfarin or other coumarin derived anticoagulants
for treatment, prophylaxis, or otherwise. Therapy with heparin, low molecular weight
heparin, fondaparinux, or direct oral anticoagulants such as rivaroxaban or apixaban
is allowed.
8. Known additional malignancy that is progressing or requires active treatment.
9. History or current evidence of any condition, therapy, or laboratory abnormality that
might confound the results of the study, interfere with the patient fs participation
for the full duration of the study or is not in the best interest of the patient to
participate, in the opinion of the treating investigator.
10. Known psychiatric or substance abuse disorders that would interfere with cooperation
with the requirements of the study.
11. Known history of human immunodeficiency virus infection.
12. History or current symptomatic pneumonitis.
13. Has clinically significant, uncontrolled heart disease and/or recent cardiac events,
including any of the following:
1. History of angina pectoris, symptomatic pericarditis, or myocardial infarction
within 12 months prior to study entry
2. History of documented congestive heart failure (New York Heart Association
functional classification III-IV)
3. Documented cardiomyopathy
4. History of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal
arrhythmias, or conduction abnormality in the previous 12 months
5. Uncontrolled hypertension defined by a systolic blood pressure (BP) =140 mmHg
and/or diastolic BP =90 mmHg, with or without antihypertensive medication over
the course of one clinic visit at intervals of =30 minutes. Initiation or
adjustment of antihypertensive medication(s) is allowed prior to screening.
14. Type 1 diabetes mellitus.
15. Uncontrolled type 2 diabetes mellitus.
16. Positive cytomegalovirus (CMV) polymerase chain reaction (PCR) test at baseline.
17. Active hepatitis B virus (HBV; chronic or acute; defined as having a known positive
hepatitis B surface antigen [HbsAg] test at the time of screening) or hepatitis C
infection requiring treatment.
- Participants with past HBV infection or resolved HBV infection (defined as the
presence of hepatitis B core antibody [HbcAb] and absence of HbsAg) are eligible
if HBV DNA is negative.
- Participants with positive for hepatitis C virus (HCV) antibody are eligible only
if PCR is negative for HCV RNA.
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