Sacituzumab Govitecan and Intrathecal Chemotherapy for Treating Leptomeningeal Metastases From Her2-negative Breast Cancer

Phase 1

Not yet recruiting

• Conditions: Leptomeningeal Metastases
• Interventions: Drug: Sacituzumab Govitecan; Drug: Pemetrexed

• Registration Number: NCT06462092
• Lead Sponsor: Guangzhou Medical University

Brief Summary

Leptomeningeal metastases is a specific pattern of central involvement in which tumor cells invade and proliferate in the subarachnoid space, and is a lethal complication of malignant tumors. Leptomeningeal metastases from Her2-negative breast cancer is still tricky to treat at present, with an overall median survival of only 3-6 months, even after aggressive treatment. This study is an open, uncontrolled phase I/II clinical study to observe the safety, feasibility, and potential efficacy of Sacituzumab Govitecan combined with pemetrexed intrathecal chemotherapy in the treatment of patients with Her2-negative breast cancer leptomeningeal metastases in search of a more effective treatment.

Detailed Description

This study is a single-arm prospective phase I/II clinical trial to observe the safety, feasibility, and potential efficacy of Sacituzumab Govitecan combined with pemetrexed intrathecal chemotherapy in the treatment of patients with Her2-negative breast cancer leptomeningeal metastases. Patients were treated with Sacituzumab Govitecan 10mg/kg, infused intravenously on days 1 and 8. Treatment cycles were every 21 days and continued until disease progression or unacceptable toxicity. Pemetrexed intrathecal chemotherapy was initiated on Day 2 after Sacituzumab Govitecan administration. Pemetrexed intrathecal chemotherapy is administered by intracerebroventricular or lumbar puncture. Pemetrexed intrathecal chemotherapy is divided into induction, consolidation and maintenance phases. Induction therapy was first performed with a single dose of 15 mg twice a week for 2 weeks for a total of 4 doses. This was followed by consolidation therapy, 1 time per week for 4 consecutive weeks for a total of 4 times. Patients whose treatment was evaluated as effective were given maintenance therapy once a month until relapse or death. A minimum of 3 patients and a maximum of 6 patients were recruited into the phase I cohort. When dose-limiting toxicity occurred in ≥2 patients, the treatment regimen was considered to be excessively side-effective, and a reduction in the intrathecal chemotherapy dose of pemetrexed to a single 10-mg dose was given, with continued enrollment of 6 consecutive patients. If DLT occurred again in ≥2 patients, the trial would be stopped. Otherwise, the study entered a phase II trial when DLT occurred in ≤1 patient.

Study Timeline

• Status Verified: 2024-06
• Study First Submitted: 2024-06-12
• Study First Submitted QC: 2024-06-12
• Last Update Submitted: 2024-06-14
• Study Start: 2024-06-15
• Study First Posted: 2024-06-17
• Last Update Posted: 2024-06-18
• Primary Completion: 2027-01-15
• Study Completion: 2027-06-15

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 34

Inclusion Criteria

1. A clear histopathologic diagnosis of breast cancer with subtype Her2- (including IHC 0, IHC 1+ or IHC 2+ and ISH negative).
2. Cerebrospinal fluid cytology diagnosis confirms the presence of leptomeningeal metastases; or imaging combined with patient symptoms and signs are consistent with the diagnosis of leptomeningeal metastases;
3. Age ≥ 18 years old;

Exclusion Criteria

1. Inadequate organ function: 1) Blood tests: ANC ≤ 1.5 x 10^9/L, PLT ≤ 90 x 10^9/L, Hb ≤ 90 g/L; 2) Blood biochemistry tests: TBIL ≥ 1.5 times the upper limit of normal; 3) ALT and AST ≥ 2.5 times the upper limit of normal;
2. Presence of serious and/or uncontrolled comorbidities that may affect participation: 1) allergy to study drugs or adjuvant materials; 2) history of immunodeficiency, including HIV-positive or other acquired or congenital immunodeficiency diseases; 3) severe concomitant diseases;
3. Pregnant and breastfeeding female patients; women of childbearing age who are unwilling to Female patients of childbearing age who are using effective contraception;
4. Any other condition that, in the opinion of the investigator, makes the patient ineligible for participation in the study.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Group	Sacituzumab Govitecan	A minimum of 3 patients and a maximum of 6 patients were recruited per cohort in phase 1 study.. When dose-limiting toxicity occurred in ≥2 patients, the treatment regimen was considered to have too many side effects, and a reduction in the intrathecal chemotherapy dose of pemetrexed to a single dose of 10 mg was given, with continued enrollment of 6 consecutive patients. If DLT occurred again in ≥2 patients, the trial would be stopped. Otherwise, the study entered a phase 2 trial when DLT occurred in ≤1 patient.
Group	Pemetrexed	A minimum of 3 patients and a maximum of 6 patients were recruited per cohort in phase 1 study.. When dose-limiting toxicity occurred in ≥2 patients, the treatment regimen was considered to have too many side effects, and a reduction in the intrathecal chemotherapy dose of pemetrexed to a single dose of 10 mg was given, with continued enrollment of 6 consecutive patients. If DLT occurred again in ≥2 patients, the trial would be stopped. Otherwise, the study entered a phase 2 trial when DLT occurred in ≤1 patient.

Primary Outcome Measures

Name	Time	Method
Maximal tolerated dose	From the beginning of the treatment until two months after the treatment.	A dose-limiting toxicity (DLT) was defined as grade 3 neurological toxicities (e.g. chemical meningitis) or other grade 4 toxicity. If more than two patients experienced a DLT, that level was considered too toxic. The maximal tolerated dose (MTD) was exceeded and an additional three patients should be treated at the next lower dose level. The MTD was defined as the dose where 0/3 or 1/6 patients experienced a DLT with at least two patients encountering DLT at the higher dose.

Secondary Outcome Measures

Name	Time	Method
Incidence of treatment-related adverse events	From the beginning of the treatment until two months after the treatment.	The incidence of treatment-related adverse events were measured for determining tolerability and safety. Adverse events (AEs) are evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE, version 4.03). Events of grade 3-5 are defined as moderate and severe adverse events.
Clinical response rate	From the beginning of the treatment until two months after the treatment or when patient died.	The Response Assessment in Neuro-Oncology (RANO) criteria proposal for response criteria of leptomeningeal metastases was used to assess the clinical response in this study.