PRIMARY OBJECTIVES:
I. To evaluate the safety profile of fulvestrant + abemaciclib + copanlisib hydrochloride (copanlisib) (FAC) and determine the recommended phase 2 dose (RP2D).
SECONDARY OBJECTIVES:
I. To assess the objective response rate (ORR = partial response \[PR\] + complete response \[CR\]) and clinical benefit rate (CBR = PR + CR + stable disease \[SD\] \>= 6 months) of FAC and medium progression free survival (PFS) with FAC.
EXPLORATORY OBJECTIVES:
I. To assess whether triplet therapy with FAC inhibits AKT phosphorylation, reduces cyclin D1, and inhibits Rb phosphorylation.
II. To assess whether the combination of abemaciclib and fulvestrant affect the copanlisib pharmacokinetics (PK).
III. To assess the objective response rate (ORR), clinical benefit rate (CBR) and median PFS in the following molecularly defined subgroups treated with FAC such as mutations in genes in the PI3K pathway (PIK3CA, AKT, PTEN etc), ESR1, TP53, or PTEN IHC loss vs not.
IV. To assess baseline and treatment induced changes in various cancer associated pathways, including but not limited to PI3K, MAPK, ER, cyclins, CDKs and CDK inhibitors; and to correlate with treatment response and progression.
V. To correlate baseline and treatment induced changes in breast cancer intrinsic subtypes (PAM50), and PI3K messenger ribonucleic acid (mRNA) signature and expression of candidate genes with treatment response and benefit from adding copanlisib.
VI. To evaluate ctDNA mutations at baseline and over time for response predictors at baseline, and clonal evolution associated with treatment.
VII. To correlate ctDNA mutation profiles with tumor sequencing, and correlate baseline ctDNA mutations, particularly in components of the PI3K pathway with treatment response, and correlate early changes in ctDNA variant allele frequencies (VAFs) with PFS, assess emergent resistant mutations at progression.
VIII. To assess resistance mechanisms to FAC at baseline and at disease progression.
IX. To examine the molecular effects of FAC on tumor and circulating markers. X. To analyze tumor infiltrating lymphocytes at baseline, during treatment, and at disease progression.
OUTLINE: This is a phase I two part, dose-escalation study of copanlisib hydrochloride and abemaciclib.
PHASE I (PART A): Patients receive copanlisib hydrochloride intravenously (IV) over 1 hour on days 1, 8, and 15 or days 1 and 15 (depending on dose level) and abemaciclib orally (PO) twice daily (BID) on on days 2-28 of cycle 1 and on days 1-28 of subsequent cycles. Patients also receive fulvestrant intramuscularly (IM) on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an echocardiography (ECHO) or multigated acquisition (MUGA) scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter.
PHASE I (PART B): Patients receive copanlisib hydrochloride IV over 1 hour on days 1, 8, and 15 or days 1 and 15 (depending on dose level) and abemaciclib PO twice daily BID for 5 days each week (2 days off). Patients also receive fulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter.
After completion of study treatment, patients are followed up every 3 months for 5 years.
\* As of November 2023, Bayer has decided to voluntarily withdraw the NDA for copanlisib, phase II portion removed.
