Pembrolizumab and Gemcitabine Chemotherapy in Leiomyosarcoma and Undifferentiated Pleomorphic Sarcoma (GEMMK)
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|ClinicalTrials.gov Identifier: NCT03123276|
Recruitment Status : Recruiting
First Posted : April 21, 2017
Last Update Posted : September 19, 2019
|First Submitted Date ICMJE||March 31, 2017|
|First Posted Date ICMJE||April 21, 2017|
|Last Update Posted Date||September 19, 2019|
|Actual Study Start Date ICMJE||November 29, 2017|
|Estimated Primary Completion Date||December 2019 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Maximum tolerated dose of gemcitabine that can be safely combined with pembrolizumab in the absence of dose limiting toxicities. [ Time Frame: completion of 1 full cycle of treatment (21 days) ]
|Original Primary Outcome Measures ICMJE
||preliminary evaluation of response by using RECIST v1.1 [ Time Frame: 2 months after the last dose ]
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE
|Current Other Pre-specified Outcome Measures
||Identify bio-markers and correlate with clinical benefit, as defined by RECIST v1.1 [ Time Frame: Up to 18 months from the first dose administered ]
|Original Other Pre-specified Outcome Measures||Same as current|
|Brief Title ICMJE||Pembrolizumab and Gemcitabine Chemotherapy in Leiomyosarcoma and Undifferentiated Pleomorphic Sarcoma|
|Official Title ICMJE||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|
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.
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:
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.
|Study Type ICMJE||Interventional|
|Study Phase ICMJE||Phase 1
|Study Design ICMJE||Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
|Study Arms ICMJE||Experimental: gemcitabine + pembrolizumab
First cohort of 6 patients may receive Gemcitabine 800 mg/m2 + Pembrolizumab 200 mg. After safety data review, if no DLTs then dose for Gemcitabine will be increased to 1000 and further 1200 mg/m2.
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Recruiting|
|Estimated Enrollment ICMJE
|Original Estimated Enrollment ICMJE||Same as current|
|Estimated Study Completion Date ICMJE||December 2019|
|Estimated Primary Completion Date||December 2019 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
|Ages ICMJE||18 Years to 99 Years (Adult, Older Adult)|
|Accepts Healthy Volunteers ICMJE||No|
|Listed Location Countries ICMJE||United Kingdom|
|Removed Location Countries|
|NCT Number ICMJE||NCT03123276|
|Other Study ID Numbers ICMJE||CCR 4541|
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||
|IPD Sharing Statement ICMJE||
|Responsible Party||Royal Marsden NHS Foundation Trust|
|Study Sponsor ICMJE||Royal Marsden NHS Foundation Trust|
|Collaborators ICMJE||Merck Sharp & Dohme Corp.|
|PRS Account||Royal Marsden NHS Foundation Trust|
|Verification Date||September 2019|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP