Trial of MEK Inhibitor and PI3K/mTOR Inhibitor in Subjects With Locally Advanced or Metastatic Solid Tumors

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Sanofi
Information provided by (Responsible Party):
EMD Serono
ClinicalTrials.gov Identifier:
NCT01390818
First received: April 18, 2011
Last updated: November 12, 2013
Last verified: November 2013
  Purpose

This research trial is testing a combination of two experimental drugs, MSC1936369B (Mitogen-activated protein extracellular signal-regulated kinase (Mek) Inhibitor) and SAR245409 (Phosphatidylinositol 3-kinase (Pi3K)/Mammalian Target of Rapamycin (mTOR) inhibitor), in the treatment of locally advanced or metastatic solid tumours. The primary purpose of the study is to determine the maximum tolerated dose of the drug combination.


Condition Intervention Phase
Locally Advanced Solid Tumor
Metastatic Solid Tumor
Breast Cancer
Non Small Cell Lung Cancer
Melanoma
Colorectal Cancer
Drug: MSC1936369B and SAR245409
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: An Open-Label, Phase Ib Dose Escalation Trial of Oral Combination Therapy With MSC1936369B and SAR245409 in Subjects With Locally Advanced or Metastatic Solid Tumors

Resource links provided by NLM:


Further study details as provided by EMD Serono:

Primary Outcome Measures:
  • The number and proportion of subjects with dose limiting toxicities [ Time Frame: 22 months ] [ Designated as safety issue: No ]
    This will be used as the primary measure for determining the Maximum Tolerated Dose (MTD) of MSC1936369B and SAR245409 combination therapy.


Secondary Outcome Measures:
  • Number of participants experiencing any treatment-emergent adverse event [ Time Frame: 34 months ] [ Designated as safety issue: No ]
  • Cmax of MSC1936369B in subjects with advanced or metastatic solid tumors [ Time Frame: 34 months ] [ Designated as safety issue: No ]
    Plasma pharmacokinetic (PK) parameter: Maximum concentration (Cmax)

  • AUC of MSC1936369B in subjects with advanced or metastatic solid tumors [ Time Frame: 34 months ] [ Designated as safety issue: No ]
    Plasma pharmacokinetic parameter: Area under the plasma concentration-time curve (AUC)

  • Tmax of MSC1936369B in subjects with advanced or metastatic solid tumors [ Time Frame: 34 months ] [ Designated as safety issue: No ]
    Plasma pharmacokinetic parameter: Time to reach maximum concentration (Tmax)

  • Cmax of SAR245409 in subjects with advanced or metastatic solid tumors [ Time Frame: 34 months ] [ Designated as safety issue: No ]
    Plasma pharmacokinetic parameter

  • AUC of SAR245409 in subjects with advanced or metastatic solid tumors [ Time Frame: 34 months ] [ Designated as safety issue: No ]
    Plasma pharmacokinetic parameter

  • Tmax of SAR245409 in subjects with advanced or metastatic solid tumors [ Time Frame: 34 months ] [ Designated as safety issue: No ]
    Plasma pharmacokinetic parameter

  • Cmax of MSC1936369B on Day 1 of Cycle 1 and Day 1 of the Drug-drug interaction (DDI) period in subjects with advanced or metastatic solid tumors [ Time Frame: 34 months ] [ Designated as safety issue: No ]
    Plasma pharmacokinetic parameter to assess the effect of SAR245409 on the pharmacokinetics of MSC1936369B

  • AUC0-24 of MSC1936369B on Day 1 of Cycle 1 and Day 1 of the DDI period in subjects with advanced or metastatic solid tumors [ Time Frame: 34 months ] [ Designated as safety issue: No ]
    Plasma pharmacokinetic parameter: Area under the plasma concentration-time curve from time zero to 24 h postdose (AUC0-24) to assess the effect of SAR245409 on the pharmacokinetics of MSC1936369B

  • Cmax of SAR245409 on Day 1 of Cycle 1 and Day 1 of the DDI period in subjects with advanced or metastatic solid tumors [ Time Frame: 34 months ] [ Designated as safety issue: No ]
    Plasma pharmacokinetic parameter to assess the effect of MSC1936369B on the pharmacokinetics of SAR245409

  • AUC0-24 of SAR245409 on Day 1 of Cycle 1 and Day 1 of the DDI period in subjects with advanced or metastatic solid tumors [ Time Frame: 34 months ] [ Designated as safety issue: No ]
    Plasma pharmacokinetic parameter to assess the effect of MSC1936369B on the pharmacokinetics of SAR245409

  • pS6 concentrations in Peripheral Blood Mononuclear Cells (PBMCs) [ Time Frame: 34 months ] [ Designated as safety issue: No ]
    Pharmacodynamic marker

  • pERK concentrations in PBMCs [ Time Frame: 34 months ] [ Designated as safety issue: No ]
    Pharmacodynamic marker

  • Number and proportion of subjects with complete tumor response, partial tumor response, or stable disease. [ Time Frame: Every 6 weeks for 34 months ] [ Designated as safety issue: No ]
    The number of patients with a complete response or partial response based on the investigator tumor evaluations performed every 6 weeks in accordance with RECIST v1.1


Estimated Enrollment: 170
Study Start Date: May 2011
Estimated Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm 1 Drug: MSC1936369B and SAR245409
Dosing of MSC1936369B (Pimasertib) and SAR245409 will occur in combination, orally, QD, and continuously in successive 21-day cycles. Dose escalation will proceed until Maximum Tolerated Dose (MTD) is reached. Once the MTD is reached, enrollment will begin in four disease-specific expansion cohorts at either the MTD or a lower dose recommended by the Safety Monitoring Committee. The four expansion cohorts will enroll patients with Breast Cancer, Non Small Cell Lung Cancer, Melanoma, and Colorectal Cancer. Patients will be considered for enrollment to the expansion cohorts based on specific gene mutations in each of the disease groups above.
Experimental: Arm 2 Drug: MSC1936369B and SAR245409
Dosing of MSC1936369B (Pimasertib) and SAR245409 will occur in combination, orally, twice daily, and continuously in successive 21-day cycles. The maximum tolerated dose of each agent will be combined with a lower dose of the combination partner.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Subject with advanced solid tumors for which there is no approved therapy:

    • Advanced solid tumor with diagnosed alteration in one or more of the following genes (PTEN, BRAF, KRAS, NRAS, PI3KCA, ErbB1, ErbB2, MET, RET, c-KIT, GNAQ, GNA11 and/or
    • A histologically or cytologically confirmed diagnosis of one of the following solid tumors: pancreatic, thyroid, colorectal, non-small cell lung, endometrial, renal, breast, ovarian carcinoma and melanoma
  2. Subject with archived tumor tissue available for transfer to the Sponsor
  3. Subject enrolled at lower dose level cohorts and MTD expansion cohorts must have tumor available for biopsy and agree to pre-treatment and on-treatment tumor biopsies
  4. Subject has measurable or evaluable disease by RECIST v1.1
  5. Subject is aged ≥ 18 years
  6. Subjects enrolled in disease specific expansion cohorts must fulfill all the inclusion/exclusion criteria listed above with the following restriction to the Inclusion Criterion number 1:

    • Relapsed or refractory KRAS or NRAS mutated metastatic NSCLC with no approved therapies, OR
    • Relapsed or refractory metastatic triple negative breast cancer defined as estrogen, progesterone and HER2 negative carcinoma of the breast with no approved therapies, OR
    • Relapsed or refractory metastatic CRC with dual KRAS and PIK3CA mutation with no approved therapies, OR
    • BRAF V600E/K mutated unresectable or metastatic melanoma after progression on BRAF inhibitors

Additional inclusion criteria also apply

Exclusion Criteria:

  1. Subject has been previously treated with a PI3K inhibitor or a MEK inhibitor and taken off treatment due to treatment related adverse events.
  2. Subject has received:

    • Chemotherapy, immunotherapy, hormonal therapy, biologic therapy, or any other anti-cancer therapy within 28 days of trial drug treatment
    • Any investigational agent within 28 days of trial drug treatment c. Extensive prior radiotherapy on more than 30% bone marrow reserves, or prior bone marrow/stem cell transplantation
  3. Subject has not recovered from toxicity due to prior therapy.
  4. Subject has poor organ and marrow function as defined in the protocol.
  5. Subject has a history of central nervous system metastases, unless subject has been previously treated for CNS metastases.
  6. Subject has a history of difficulty swallowing, malabsorption or other chronic gastrointestinal disease .
  7. Subject has a history of recent major surgery or trauma within the last 28 days.
  8. Subject has participated in another clinical trial within the past 30 days.

Additional exclusion criteria also apply

  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01390818

Locations
United States, Arizona
Pinnacle Oncology Hematology
Scottsdale, Arizona, United States, 85258
United States, California
Cedars Sinai Medical Center
Los Angeles, California, United States, 90048
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States
United States, New York
Memorial Sloan Kettering Cancer Center
New York, New York, United States, 10065
United States, Tennessee
Sarah Cannon Research Institute
Nashville, Tennessee, United States, 37205
United States, Texas
Cancer Therapy and Research Center
San Antonio, Texas, United States, 78229
Italy
Merck Serono Research Site
Milan, Italy
Spain
Merck Serono Research Site
Madrid, Spain
Sponsors and Collaborators
EMD Serono
Sanofi
Investigators
Principal Investigator: Rebecca S Heist, MD, MPH Massachusetts General Hospital
  More Information

No publications provided

Responsible Party: EMD Serono
ClinicalTrials.gov Identifier: NCT01390818     History of Changes
Other Study ID Numbers: EMR 200066-006
Study First Received: April 18, 2011
Last Updated: November 12, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by EMD Serono:
MEK inhibitor (Pimasertib)
PI3K/mTOR Inhibitor
Solid Tumor
Phase I

Additional relevant MeSH terms:
Breast Neoplasms
Carcinoma, Non-Small-Cell Lung
Colorectal Neoplasms
Lung Neoplasms
Melanoma
Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Lung Diseases
Respiratory Tract Diseases
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Nevi and Melanomas
Sirolimus

ClinicalTrials.gov processed this record on April 15, 2014