ATI-2231 With in Advanced Solid Tumor Malignancies Followed by ATI-2231 in Combination With Capecitabine in Patients With Hormone Receptor-positive and HER2 Negative Metastatic Breast Cancer

• Status: Not yet recruiting
• Trial end date: 2030-10-01
• Target enrollment: 0
• Participant gender: All

Summary

Phase Ia is a dose-escalation Phase I study of ATI-2231 monotherapy, using 3 plus 3 design, with the primary endpoint of adverse events. Phase Ib tests the safety and tolerability of ATI-2231 in combination with chemotherapy (capecitabine) at recommended phase II dose (RP2D) obtained from Phase Ia. This is followed by the randomized Phase II study of ATI-2231 in combination with chemotherapy testing the hypothesis that the combination of chemotherapy (capecitabine) and ATI-2231 will reduce bone turnover, improve clinical efficacy including progression-free survival (PFS), improve patient bone density and patient quality of life.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Washington University School of Medicine
• Collaborators: Aclaris Therapeutics, Inc.; United States Department of Defense
• Treatments: Capecitabine; Denosumab; Diphosphonates

Criteria

Inclusion Criteria:

• Phase Ia: Biopsy-proven advanced solid tumor malignancy with refractory disease.

• Phase Ib: Biopsy-proven hormone receptor-positive, HER2 negative metastatic breast cancer with or without bone metastasis by current ASCO/CAP guidelines.

• Phase II: Biopsy-proven hormone receptor-positive, HER2 negative metastatic breast cancer with progressive bone metastasis per the latest tumor imaging studies.

• Measurable or non-measurable but evaluable disease by RECIST v 1.1.

• No more than one prior chemotherapy for metastatic disease (Phase 1b and Phase II only). There are no limits on prior endocrine therapy-based regimens.

Note: History of trastuzumab deruxtecan treatment is not a required inclusion criteria as this drug is currently approved in HER2-low metastatic breast cancer following one line of chemotherapy in the metastatic setting.

• Phase Ib: Planning to start or on stable doses of capecitabine (capecitabine cohort:

no less than 1000 mg/m2 BID, 14 days on and 7 days off)

• Phase II: Candidate for initiating capecitabine treatment per physician decision and history of prior endocrine therapy with CDK4/6 inhibitor.

• At least 4 weeks have passed (i.e., washout period of 4 weeks is required) with denosumab and zoledronic acid, before the start of study treatment if the patient was on these drugs before enrollment, including patients in the Phase II study.

• At least 6 months of therapy with bisphosphonate or denosumab for bone metastasis is required in patients who received these agents prior to enrolling to the Phase II study only.

• Phase Ib: Washout from prior chemotherapy other than capecitabine (for the capecitabine cohort) for 3 weeks or passed 5 half-lives and recovered adverse events (AEs) to Grade 1 (except for alopecia).

• Phase II: Washout from prior chemotherapy for 3 weeks or passed 5 half-lives and recovered AEs to Grade 1 (except for alopecia).

• A washout period of 1 week is required from the completion of radiation therapy.

• At least 18 years of age.

• ECOG performance status ≤ 2

• Life expectancy of at least 12 weeks.

• Adequate bone marrow and organ function as defined below:

• Leukocytes ≥ 3,000/mcL

• Absolute neutrophil count (ANC) ≥ 1,500/mcL

• Platelets ≥ 100,000/mcL

• Total bilirubin ≤ 1.5 x IULN

• AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN

• Creatinine clearance > 60 mL/min by Cockcroft-Gault

• The effects of ATI-2231on the developing human fetus are unknown. For this reason, women of childbearing potential and men who are heterosexually active must agree to use adequate contraception as specified in the protocol. Contraception should continue for 1 month (for women) or 3 months (for men) after the end of treatment. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.

• Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).

Exclusion Criteria:

• A history of other malignancy with the exception of malignancies for which all treatment was completed at least 2 years before registration and the patient has no evidence of disease (Phase II only).

• Currently receiving any other investigational agents.

• Untreated brain metastases. Patients with treated brain metastases are eligible if they show no evidence of progression and are off steroids or on stable/decreasing steroid dose.

• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to ATI-2231 or other agents used in the study.

• History of acute, untreated skeletal related events (SRE) or active untreated SRE or a change or an anticipated change in the SOC antiresorptive agents after entering the study (Phase II only).

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia.

• Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of study entry.

• Patients with known HIV are eligible unless their CD4+ T-cell counts are < 350 cells/mcL or they have a history of AIDS-defining opportunistic infection within the 12 months prior to registration. Concurrent treatment with effective ART according to DHHS treatment guidelines is recommended.