Spots Global Cancer Trial Database for Study Evaluating Efficacy & Safety of Afuresertib Plus Fulvestrant in Patients w/ Locally Advanced or Metastatic HR+/HER2- Breast Cancer

Study Description

Brief Summary: Study LAE205INT3101 is a Phase Ib/III study to evaluate the efficacy and safety of the combination therapy with afuresertib plus fulvestrant (afuresertib/placebo plus fulvestrant in Phase III) in patients with HR+/HER2- breast cancer who have failed 1 to 2 prior lines of endocrine therapy, and/or CDK4/6 inhibitor (up to 1 therapy), and/or chemotherapy (up to 1 chemotherapy) as described in the inclusion criteria.

Detailed Description: Eligible patients for this study must have either (1) progressive disease whilst receiving an endocrine therapy (AI or a SERM), and/or a CDK4/6 inhibitor for locally advanced or metastatic disease; or (2) relapsed with metastatic disease whilst receiving an ET (AI or SERM), and/or a CDK4/6 inhibitor, and/or chemotherapy in adjuvant setting. No more than 2 prior lines of systemic treatments for locally advanced or metastatic disease are allowed for this study, including 1-2 prior lines of endocrine therapy, with/without CDK4/6 inhibitor (up to 1 therapy), and/or chemotherapy (up to 1 therapy). The Phase Ib part is a single-arm, open-label, "proof-of-concept" study to evaluate anti-tumor efficacy, safety, tolerability and pharmacokinetics of the combination therapy with afuresertib plus fulvestrant. Twenty patients will be enrolled in this part. There will be a safety run-in period during the first 28-days of treatment (Cycle 1) of the first 6 enrolled patients to evaluate the safety of the initial treatment doses of the combination therapy, and to make dose modification if severe treatment-related toxicities occur. Patients will receive afuresertib 125 mg PO, QD in combination with fulvestrant 500 mg IM, D1, 15 in Cycle 1, and fulvestrant 500 mg IM, D1 Q4W in the subsequent cycles. If no severe treatment-related toxicity is observed during the safety-run-in period, based on investigator's clinical judgements, the enrollment will resume for the remaining 14 patients. If any treatment-related toxicity (≥ grade 3) is observed in 1 of the 6 patients (e.g., thrombocytopenia, neutropenia, hyperglycemia, rash, diarrhea, fatigue, etc.), and is not resolved within 7 days in spite of active management per institutional standard of care, the dose of afuresertib for all patients participating in the safety run-in will be reduced to 125 mg, D1-21, Q4W (if afuresertib alone or both afuresertib and fulvestrant are the potential causal agents) or the dose of fulvestrant reduced to 250 mg IM D1,15 in Cycle 1, and 250 mg IM D1 Q4W (if fulvestrant is the potential causal agent) in the subsequent cycles. In the event that the causal relationship between study drugs and the observed AE could not be reasonably established, reduction of afuresertib should take precedence based on the Safety Review Committee (SRC) decision. For the primary efficacy objective of the Phase Ib part, the primary endpoint is the investigator-assessed ORR based on RECIST 1.1 of the afuresertib plus fulvestrant combination therapy in HR+/HER2- BC. The PK parameters of the afuresertib in the combination treatment (e.g., Cmax, AUC(0-t), AUC(0-inf), Tmax, t1/2, etc.) will be assessed in all patients in the Phase Ib part based on plasma levels of afuresertib, obtained at different timepoints as described in the tables of Schedule of Activities (SoA). The efficacy and safety data analysis will be conducted after the completion of the Phase Ib part. If the efficacy and safety data of the afuresertib plus fulvestrant combination therapy support a positive benefit/risk ratio, this combination regimen will be further evaluated for its efficacy and safety in the Phase III part. If there is insufficient evidence of efficacy for the study treatment at the end of the Phase Ib part, the sponsor and the investigators must reach a consensus on whether to expand patient enrollment to continue the Phase Ib study. The Phase III part is a multi-center, randomized, double-blind, placebo-controlled pivotal study with two parallel treatment arms to further assess the anti-tumor efficacy and safety of afuresertib combined with fulvestrant (experimental arm) versus placebo combined with fulvestrant (control arm) in patients with HR+/HER2- BC who have failed 1 to 2 prior lines of ET, and/or CDK4/6 inhibitor (up to 1 therapy), and/or chemotherapy (up to 1 chemotherapy). A total of 252 patients will be randomized in a 1:1 ratio to the two parallel treatment arms, afuresertib plus fulvestrant and placebo plus fulvestrant. Randomization will be based on stratification factors, including prior chemotherapy (yes or no), prior CDK4/6 inhibitor therapy (yes or no). The doses of the study treatment will be based on doses and schedule established in the Phase Ib part. The primary endpoint is the investigator-assessed PFS based on RECIST 1.1 of the experimental arm and control arm. The major secondary endpoints include the OS, ORR, DOR, DCR and safety.

Keywords

Eligibility

Minimum Age: 18 Years

Eligible Ages: ADULT, OLDER_ADULT

Sex: ALL

Healthy Volunteers: No

Locations

Contact Details

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