Pembrolizumab and Gemcitabine Chemotherapy in Leiomyosarcoma and Undifferentiated Pleomorphic Sarcoma — GEMMK  

Sarcoma Clinical Trial

Official title: A Phase I Study to Assess the Safety and Tolerability of Pembrolizumab in Combination With Fixed Rate Gemcitabine Chemotherapy in Patients With Leiomyosarcoma and Undifferentiated Pleomorphic Sarcoma

Status Active, not recruiting

Clinical Trial Summary

Soft tissue sarcomas (STS) are a group of rare mesenchymal neoplasms affecting all ages. STS most commonly present as localised disease but despite surgery and adjuvant treatment more than half of patients will develop recurrent or metastatic disease. Leiomyosarcoma (LMS), a malignancy of smooth muscle, is one of the most common STS and undifferentiated pleomorphic sarcoma (UPS) is a common sarcoma sub-type with aggressive symptoms.

Recent studies have demonstrated reasonable sensitivity of LMS to gemcitabine monotherapy with an objective response rate of 8-19%. However the overall survival is still only about 12 months which illustrates the critical clinical need for improved therapies for advanced STS and sarcoma in general.

In this study the investigators propose to combine the immune synapse checkpoint inhibitor with the cytotoxic and immune modulating agent, gemcitabine. It is hoped that this dual immunomodulatory approach will enhance the effect of pembrolizumab on PD-L1 expressing LMS and UPS, leading to a safe treatment with patient outcomes. This is a two part, phase I, single centre dose escalation and dose expansion study in the total of 24 patients with newly diagnosed metastatic or inoperable LMS and UPS. There will be approximately 12 patients in the dose escalation cohort (part A) and the starting dose will be a fixed dose rate (FDR) gemcitabine of 800 mg/m2 on day 1 and 8 of 21 days cycles in combination of 200 mg of pembrolizumab given as an infusion on day 1 every 3 weeks. The MTD cohort (part B) will then be expanded to a total of 12 patients in order to further evaluate the safety and tolerability of that dose as well as to preliminarily assess response to therapy.

The study is sponsored by Royal Marsden NHS Foundation trust and the funding for the study is provided by Merck Sharp & Dohme Limited.

Clinical Trial Description

This is a two part, phase I, single centre dose escalation and dose expansion study to establish the safety, tolerability and pharmacokinetics of pembrolizumab in combination with different dose levels of fixed dose rate gemcitabine in patients with newly diagnosed metastatic or inoperable leiomyosarcoma and undifferentiated pleomorphic sarcoma (UPS), for whom gemcitabine monotherapy is deemed appropriate, or in patients with previously treated leiomyosarcoma and undifferentiated pleomorphic sarcoma, not including gemcitabine, with disease progression documented in the 12 weeks prior to enrolment.

There will be a maximum of 18 patients in the dose-escalation cohort (part A) and the starting dose will be a fixed dose rate (FDR) gemcitabine of 800 mg/m2 on day 1 and 8 of 21 days cycles in combination of 200 mg of pembrolizumab given as an infusion on day 1 every 3 weeks. There will be a minimum of three and a maximum of six evaluable patients entered per dose cohort and each patient will continue to receive treatment cycles of gemcitabine in combination with pembrolizumab for as long as he/she is, in the opinion of the investigator, deriving clinical benefit and continues to meet re-treatment criteria. Treatment will continue until disease progression or is stopped because of toxicity. There will be an option to continue pembrolizumab alone in patients with SD or response who stop gemcitabine for toxicity before completing 6 cycles of combination therapy. During the dose-escalation phase, safety, tolerability, biological and clinical activity will be assessed and the maximum tolerated dose (MTD) will be established.

The MTD cohort (part B) will then be expanded to a total of 12 patients in order to further evaluate the safety and tolerability of that dose as well as to preliminarily assess response to therapy.

A mandatory tumour biopsy will be collected prior to the start of treatment for pre-treatment testing for PD-L1 expression, Immunophenotyping and extent and localization of tumour infiltrating lymphocytes and following 3 cycles of therapy for analysis of potential markers of tumour response on post-treatment tissue. Additional mandatory bloods will be collected for analysis of potential circulating immune markers. Patient genetic material will also be collected for analysis of potential markers of tumour response and future pharmacogenetic analyses. Provision of genetic material is not mandatory for participation in the main study.

Part A: Dose escalation cohort

Part A will be the dose escalation phase. Gemcitabine doses will be escalated (or de-escalated) until the non-tolerated dose (NTD) is attained and a maximum tolerated dose (MTD) is defined. A maximum of 18 patients will be recruited in cohorts of 3 to 6 patients as part of a toxicity rule-based 3+3 design. The total number of patients will depend upon the number of dose escalations and toxicities observed.

The starting dose (dose level 1) will be 800 mg/m2 of FDR gemcitabine given by 120 min IV infusion on Day 1 and Day 8 of each 3 week cycle (see Rationale for choice of starting doses). Pembrolizumab will be administered as a 200 mg IV infusion on Day 1 following the infusion of FDR gemcitabine. Pembrolizumab infusions will be repeated every 3 weeks. Each dose escalation cohort will consist of a minimum of three and a maximum of six patients.

A dose-limiting toxicity is defined as:

• Neutropenia <0.5 x 109/L for >5 days . This must be confirmed with repeat blood tests at the Royal Marsden Hospital within 6 days of the diagnosis of neutropenia.

• Febrile neutropaenia as per definition by ESMO (>38.3°C or two consecutive readings of >38.0°C for 2 hours and an absolute neutrophil count (ANC) of <0.5 x 109/L or expected to fall below <0.5 x 109/L)

• Thrombocytopenia <25 x 109/L.

• Any non-haematological CTCAE Grade 3 or 4 toxicity that is, in the opinion of the investigator, clinically significant.

The toxicities listed above must be, in the investigator's opinion, likely to be causally linked with the administration of Gemcitabine.

In the unlikely event that dose-limiting toxicity (DLT) occurs at the proposed starting dose and that dose is deemed intolerable, a second cohort of patients will be recruited and a dose of 600 mg/m2 (dose level -1). If no dose limiting toxicity (DLT) is documented, the FDR gemcitabine dose will be escalated to 1000 mg/m2 and subsequently to 1200 mg/m2 unless 2 or more patients in a single cohort have experienced DLT.

If the first patient does not experience dose-limiting toxicity by Day 14 of the first treatment cycle, two additional patients may be entered. Three patients must complete one full cycle of treatment (to day 21 of cycle 1) for a dose-escalation decision to be made.

If one of the first three patients in a cohort experiences a DLT during the first cycle, the cohort will be expanded to six patients. If 2/3 or 2/6 patients in a cohort experience DLT during the first cycle, that dose will be considered intolerable, no further dose-escalations will occur and cohort expansion of the next lowest dose (the presumed maximum tolerated dose

• MTD) will commence. Only toxicities occurring during the first treatment cycle will be taken in to account for dose escalation decisions.

If a patient withdraws or is withdrawn for reasons other than DLT prior to completing Cycle 1, the patient will be replaced.

Part B: Maximum tolerated dose cohort

A total of 12 additional patients will be recruited and dosed at the MTD identified in Part A in order to ensure the tolerability and biological activity of gemcitabine in combination with pembrolizumab as well to preliminarily assess response to therapy.

Evaluation of tumour response will be according to RECIST v1.1 (Response Evaluation Criteria in Solid Tumours) criteria. The RECIST v1.1 guidelines for measurable, non-measurable, target and non-target lesions and the objective tumour response criteria (complete response, partial response, stable disease or progression of disease) are presented in the Appendix.

All patients will have imaging performed at the end of the 3rd and the 6th cycle. After cycle 6, RECIST evaluation will be performed at the end of every third cycle for the duration of the entire study, or more frequently if it deemed necessary by the Investigator. ;

Related Conditions & MeSH terms

• Histiocytoma, Malignant Fibrous
• Leiomyosarcoma
• Sarcoma

• NCT number: NCT03123276
• Study type: Interventional
• Source: Royal Marsden NHS Foundation Trust
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: November 29, 2017
• Completion date: February 5, 2023