Title
A Phase 1a/1b Open-Label Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Efficacy of BBO-10203 in Subjects with Advanced Solid Tumors (The BREAKER-101 Trial)

Description
First in human study to evaluate the safety, tolerability, and pharmacokinetics (PK) of BBO-10203, a PI3Ka:RAS breaker, alone and in combination with other anti-cancer agents in patients with advanced solid tumors.

Objective
Primary:
Phase 1a Dose Escalation: BBO-10203 Monotherapy
-To evaluate the safety and tolerability of BBO-10203, an inhibitor of the PI3K?:RAS interaction, in subjects with locally advanced unresectable or metastatic (ie, advanced) HER2-positive BC; HR-positive, HER2-negative BC; KRAS mutant NSCLC; and KRAS mutant CRC.

Phase 1a Dose Escalation:
BBO-10203 + Trastuzumab in Subjects with HER2-positive aBC;
BBO-10203 + Fulvestrant +/- Ribociclib in Subjects with HR-positive HER2-negative aBC;
BBO-10203 + FOLFOX + Bevacizumab in Subjects with KRAS mutant aCRC

-To determine the recommended dose of BBO-10203 to be administered in combination with:
Trastuzumab in subjects with HER2-positive aBC
Fulvestrant +/- ribociclib in subjects with HR-positive HER2-negative aBC
FOLFOX + bevacizumab in subjects with KRAS mutant aCRC
in Phase 1b Dose Expansion by evaluation of totality of safety, PK, and efficacy data.

Phase 1b Dose Expansion: BBO-10203 + Trastuzumab in Subjects with HER2-positive aBC;
BBO-10203 + Fulvestrant +/- Ribociclib in Subjects with HR-positive HER2-negative aBC;
BBO-10203 + FOLFOX + Bevacizumab in Subjects with KRAS mutant aCRC; BBO-10203 Monotherapy in HER2-positive aBC

-To determine the safety and tolerability and evaluate antitumor activity of BBO-10203 monotherapy in subjects with HER2-positive aBC and in combination with:
Trastuzumab in subjects with HER2-positive aBC.
Fulvestrant +/- ribociclib in subjects with HR-positive HER2-negative aBC.
FOLFOX + bevacizumab in subjects with KRAS mutant aCRC.

Treatment This is an open-label, multi-center Phase 1a/1b study designed to evaluate the safety, tolerability, preliminary antitumor activity, and PK of BBO-10203 as a single agent and in combination with Trastuzumab, Fulvestrant +/- Ribociclib, or FOLFOX + Bevacizumab in patients with locally advanced unresectable or metastatic (ie, advanced) solid tumors. The study includes a dose escalation phase and an expansion phase.

Key Eligibility Inclusion Criteria:

Locally advanced and unresectable or metastatic HER2-positive advanced breast cancer (aBC), HR-positive/HER2-negative advanced breast cancer, KRAS mutant advanced colorectal cancer (aCRC), or KRAS mutant advanced non-small cell lung cancer (aNSCLC)

Measurable disease by RECIST v1.1 (except for HR-positive HER2-negative aBC where evaluable bone-only disease is permitted)

Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1

Adequate LVEF assessed by ECHO or MUGA (BBO-10203 + Trastuzumab cohorts only)

Stable brain metastases

Patients with HER2-positive aBC: Must have had at least 2 prior lines of anti-HER2-directed therapy. Only 1 prior line is acceptable where there is no other regionally available standard of care (SoC)

Monotherapy Cohort patients with HR-positive, HER2-negative aBC, KRAS mutant aCRC or aNSCLC: Must have progression on, or disease recurrence after at least one line of SOC treatment or in the opinion of the investigator, would be unlikely to tolerate or derive clinically meaningful benefit from SoC therapy

BBO-10203 + Fulvestrant combination cohort patients with HR-positive, HER2-negative aBC: confirmed PIK3CA mutation, must have been treated with a CDK4/6i

BBO-10203 + Fulvestrant + ribociclib combination cohort patients with HR-positive, HER2-negative aBC: confirmed PIK3CA mutation, no prior systemic therapy in the aBC setting permitted

BBO-10203 + FOLFOX + Bevacizumab combination cohort patients with KRAS mutant aCRC: One prior line of irinotecan-containing therapy for locally advanced or metastatic CRC is allowed but not required

Applicable Disease Sites
Breast; Colon and Rectum; Lung

Participating Institutions
UW Health Eastpark Medical Center; UW Health University Hospital