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

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.

* Participants with positive for hepatitis C virus (HCV) antibody are eligible only if PCR is negative for HCV RNA.

What this study is about