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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 : December 11, 2017
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Royal Marsden NHS Foundation Trust

Brief 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.


Condition or disease Intervention/treatment Phase
Sarcoma Drug: Pembrolizumab Drug: Gemcitabine Phase 1 Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
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
Actual Study Start Date : November 29, 2017
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2019


Arm Intervention/treatment
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.
Drug: Pembrolizumab
humanized IgG4 PD-1 blocking antibody
Other Name: Keytruda

Drug: Gemcitabine
Doses of 800, 1000 and 1200 mg/m2 will be used in dose escalation phase.




Primary Outcome Measures :
  1. preliminary evaluation of response by using RECIST v1.1 [ Time Frame: 2 months after the last dose ]
    primary outcome


Secondary Outcome Measures :
  1. Immunophenotyping of biopsies (FFPE samples, density and phenotype of tumour infiltrating lymphocytes; CD3+, CD8+, CD45, FoxP3 and PD1) [ Time Frame: Pre and post-treatment (9 weeks after end of treatment) ]
    Secondary outcome

  2. Location of tumour infiltrating lymphocytes (proximity to tumour cells and location relative to the microvasculature; Prototype analysis software at ICR) [ Time Frame: Up to 18 months from the first dose administered ]
    Secondary outcome

  3. Response stratification according to tumour PD-L1 expression [ Time Frame: 6 and 12 months ]
    Secondary outcome


Other Outcome Measures:
  1. 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 ]
    Exploratory outcome



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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Have a histologically confirmed case of undifferentiated pleomorphic sarcoma or leiomyosarcoma
  2. Be able to provide archival tissue for pathology review and confirmation of a diagnosis of leiomyosarcoma or undifferentiated pleomorphic sarcoma
  3. Have biopsiable disease in order to permit acquisition of mandatory paired tumour biopsies for analysis of immunomodulation.
  4. Be willing to agree to a core biopsy to be done prior to enrolling and following 9 weeks of treatment.
  5. Be willing and able to provide written informed consent/assent for the trial.
  6. Be over 18 years of age on day of signing informed consent.
  7. Have a performance status of 0 or 1 on the ECOG Performance Scale.
  8. Have measurable disease based on RECIST 1.1.
  9. Have a life expectancy of >12 weeks
  10. Demonstrate adequate organ function as defined in the protocol, all screening labs should be performed within 10 days of treatment initiation.
  11. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
  12. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an adequate method of contraception as outlined in Section 5.7.2 - Contraception, for the course of the study through 120 days after the last dose of study medication.

    Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

  13. Male subjects of childbearing potential (Section 5.7.1) must agree to use an adequate method of contraception as outlined in Section 5.7.1- Contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy.

Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

Exclusion Criteria:

  1. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
  2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
  3. Has a known history of active TB (Bacillus Tuberculosis)
  4. Hypersensitivity to pembrolizumab or any of its excipients.
  5. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
  6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.

    Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.

    Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.

  7. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
  8. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
  9. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
  10. Has known history of, or any evidence of active, non-infectious pneumonitis.
  11. Has an active infection requiring systemic therapy.
  12. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
  13. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  14. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
  15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
  16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
  17. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
  18. Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03123276


Contacts
Contact: Dale Smith 02089156765 gemmk.trial@rmh.nhs.uk
Contact: Victoria Pittordou 02089156765 gemmk.trial@rmh.nhs.uk

Locations
United Kingdom
Royal Marsden Recruiting
London, United Kingdom
Contact: Robin Jones       robin.jones4@nhs.net   
Sponsors and Collaborators
Royal Marsden NHS Foundation Trust
Merck Sharp & Dohme Corp.
Investigators
Principal Investigator: Robin Jones Royal Marsden NHS Foundation Trust

Responsible Party: Royal Marsden NHS Foundation Trust
ClinicalTrials.gov Identifier: NCT03123276     History of Changes
Other Study ID Numbers: CCR 4541
First Posted: April 21, 2017    Key Record Dates
Last Update Posted: December 11, 2017
Last Verified: December 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Histiocytoma, Malignant Fibrous
Neoplasms, Connective and Soft Tissue
Neoplasms, Muscle Tissue
Histiocytoma
Neoplasms, Fibrous Tissue
Neoplasms, Connective Tissue
Sarcoma
Leiomyosarcoma
Neoplasms by Histologic Type
Neoplasms
Gemcitabine
Pembrolizumab
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs