Phase 2 Study of PI3K Inhibitor Copanlisib in Combination With Fulvestrant in Selected ER+ and/or PR+ Cancers With PI3K (PIK3CA, PIK3R1) and/or PTEN Alterations

The purpose of this study is to evaluate the efficacy and safety of copanlisib in combination with fulvestrant in advanced hormone receptor-positive (HR+) solid tumors harboring alterations that activate the Phosphatidylinositol-3 kinase (PI3K) pathway.

Part 1: Dose confirmation:

Primary Objective:

• To evaluate the safety, tolerability, and dose-limiting toxicities (DLT) of copanlisib 60 mg administered intravenously (IV) on Days 1, 8 and 15 in combination with fulvestrant 500 mg administered intramuscularly (IM) on Day 1 and Day 15 of Cycle 1, and then on Day 1 of each subsequent 28-day cycle to confirm the recommended phase 2 doses (RP2D) of the combination therapy.

Secondary objective:

* To assess the efficacy of copanlisib administered in combination with fulvestrant as outlined in Part 2 by evaluating the objective response rate (ORR).
* To evaluate additional efficacy measures such as progression-free survival (PFS) and overall survival (OS) of copanlisib in combination with fulvestrant.

Exploratory Objectives:

• To investigate target engagement, clonal evolution, and mechanisms of resistance using tissue and liquid biopsies utilizing circulating tumor DNA (ctDNA) as outlined in Part 2.

Part 2: Dose expansion:

Primary objectives:

• To assess the efficacy of copanlisib administered in combination with fulvestrant as outlined above by evaluating the objective response rate (ORR). Patients enrolled for Part 1 will be included in this efficacy analysis.

Secondary Objectives:

* To evaluate additional efficacy measures such as PFS and OS of copanlisib in combination with fulvestrant.
* To evaluate the safety and tolerability of copanlisib in combination with fulvestrant.

Exploratory Objectives:

• To investigate target engagement, clonal evolution, and mechanisms of resistance using tissue and liquid biopsies utilizing ctDNA.

Eligibility Criteria:
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.