Testing the Addition of Copanlisib to Usual Treatment (Fulvestrant and Abemaciclib) in Metastatic Breast Cancer

Description

PRIMARY OBJECTIVES:

I. To evaluate the safety profile of fulvestrant + abemaciclib + copanlisib hydrochloride (copanlisib) (FAC) and determine the recommended phase 2 dose (RP2D).

II. To determine if FAC is superior to fulvestrant + abemaciclib (FA) using progression-free survival (PFS) as an endpoint.

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 versus (vs.) FA.

II. To compare the median PFS between FAC and FA arms in the following subgroups:

IIa. Tumor PIK3CA/PTEN altered (PIK3CA mutation or PTEN mutation/PTEN loss). IIb. Tumor PIK3CA/PTEN not altered (wild-type PIK3CA and PTEN and without PTEN loss).

IIc. Tumor phosphorylated (p)AKT levels (above or below the median). III. To assess whether triplet therapy with FAC inhibits AKT phosphorylation, reduces cyclin D1, and is more effective than FA in inhibiting Rb phosphorylation.

EXPLORATORY OBJECTIVES:

I. To assess whether the combination of abemaciclib and fulvestrant affect the copanlisib pharmacokinetics (PK).

II. To assess the median PFS in the following molecularly defined subgroups treated with either FAC or FA:

IIa. Tumor PIK3CA mutation vs. not. IIb. Tumor PTEN mutation/PTEN loss vs. not. IIc. Circulating tumor deoxyribonucleic acid (DNA) (ctDNA) PIK3CA mutation vs. not.

IId. CtDNA PI3K/PTEN mutation vs. not. IIe. CtDNA ESR1 mutation vs. not. III. 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.

IV. 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.

V. To evaluate ctDNA mutations at baseline and over time for response predictors at baseline, and clonal evolution associated with treatment.

VI. 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.

VII. To assess resistance mechanisms to FA and FAC at baseline and at disease progression.

VIII. To examine the molecular effects of FA and FAC on tumor and circulating markers.

IX. To analyze tumor infiltrating lymphocytes at baseline, during treatment, and at disease progression.

X. To assess whether copanlisib affects abemaciclib pharmacokinetics (PK).

OUTLINE: This is a phase I two part, dose-escalation study of copanlisib hydrochloride and abemaciclib, followed by a phase II study.

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.

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.

PHASE II: Patients are randomized to 1 of 2 arms.

ARM I (FAC): Patients receive copanlisib hydrochloride as in phase I. Patients also receive abemaciclib PO BID as in phase I part B and fulvestrant IM on days 1 and 15 of cycle 1 and day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II (FA): Patients receive abemaciclib PO BID on days 1-28 and fulvestrant IM on days 1 and 15 of cycle 1 and day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 5 years.

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