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

Anatomic Stage IV Breast Cancer AJCC v8 Clinical Trial

Official title: A Randomized Phase I/II Trial of Fulvestrant and Abemaciclib in Combination With Copanlisib (FAC) Versus Fulvestrant and Abemaciclib Alone (FA) for Endocrine-Resistant, Hormone Receptor Positive, HER2 Negative Metastatic Breast Cancer (FAC vs FA)

Status Active, not recruiting

Clinical Trial Summary

This phase I/II trial studies the effects (good and bad) of adding copanlisib to the usual therapy of fulvestrant and abemaciclib in treating patients with hormone receptor positive and HER2 negative breast cancer that has spread from where it first started (breast) to other places in the body (metastatic). Some breast cancer cells have receptors for the hormones estrogen or progesterone. These cells are hormone receptor positive and they need estrogen or progesterone to grow. This can affect how the cancer is treated. Hormone therapy using fulvestrant may fight breast cancer by blocking the use of estrogen by the tumor cells. Abemaciclib and copanlisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Adding copanlisib to the usual therapy of fulvestrant and abemaciclib may work better than giving fulvestrant and abemaciclib alone in treating patients with breast cancer.

Clinical Trial 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. 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.

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. 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.

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. 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. ;

Related Conditions & MeSH terms

• Anatomic Stage IV Breast Cancer AJCC v8
• Breast Neoplasms
• Carcinoma
• Metastatic Breast Carcinoma
• Recurrent Breast Carcinoma

• NCT number: NCT03939897
• Study type: Interventional
• Source: National Cancer Institute (NCI)
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: June 17, 2020
• Completion date: March 11, 2025