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

This study has been completed.
Sponsor:
Collaborator:
Sanofi
Information provided by (Responsible Party):
EMD Serono
ClinicalTrials.gov Identifier:
NCT01390818
First received: April 18, 2011
Last updated: July 8, 2014
Last verified: July 2014

April 18, 2011
July 8, 2014
May 2011
May 2014   (final data collection date for primary outcome measure)
Number of subjects with dose limiting toxicities [ Time Frame: 22 months ] [ Designated as safety issue: Yes ]
This will be used as the primary measure for determining the Maximum Tolerated Dose (MTD) of MSC1936369B and SAR245409 combination therapy.
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.
Complete list of historical versions of study NCT01390818 on ClinicalTrials.gov Archive Site
  • Number of subjects experiencing any treatment-emergent adverse events [ Time Frame: 34 months ] [ Designated as safety issue: Yes ]
  • Pharmacokinetics parameters in plasma: Cmax, tmax, AUC (0-24), AUC (0-tau), AUC (0-infinity), t1/2, CL/f, CLss/f, Vz/f, Vss/f, Racc(AUC), and Racc(Cmax) for MSC1936369B [ Time Frame: 34 months ] [ Designated as safety issue: No ]
  • Pharmacokinetics parameters in plasma: Cmax, tmax, AUC (0-24), AUC (0-tau), AUC (0-infinity), t1/2, CL/f, CLss/f, Vz/f, Vss/f, Racc(AUC), and Racc(Cmax) for SAR245409 [ Time Frame: 34 months ] [ Designated as safety issue: No ]
  • 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 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 subjects with a complete response or partial response based on the investigator tumor evaluations performed every 6 weeks in accordance with RECIST v1.1.
  • Number of participants experiencing any treatment-emergent adverse event [ Time Frame: 22 months ] [ Designated as safety issue: No ]
  • Cmax of MSC1936369B in subjects with advanced or metastatic solid tumors [ Time Frame: 22 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: 22 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: 22 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: 22 months ] [ Designated as safety issue: No ]
    Plasma pharmacokinetic parameter
  • AUC of SAR245409 in subjects with advanced or metastatic solid tumors [ Time Frame: 22 months ] [ Designated as safety issue: No ]
    Plasma pharmacokinetic parameter
  • Tmax of SAR245409 in subjects with advanced or metastatic solid tumors [ Time Frame: 22 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: 22 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: 22 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: 22 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: 22 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: 22 months ] [ Designated as safety issue: No ]
    Pharmacodynamic marker
  • pERK concentrations in PBMCs [ Time Frame: 22 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: 22 months ] [ Designated as safety issue: No ]
    Clinical benefit based on the Investigator tumor evaluations performed every 6 weeks in accordance with Response Evaluation Criteria In Solid Tumors (RECIST) v1.1
Not Provided
Not Provided
 
Trial of MEK Inhibitor and PI3K/mTOR Inhibitor in Subjects With Locally Advanced or Metastatic Solid Tumors
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

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 tumors. The primary purpose of the study is to determine the maximum tolerated dose of the drug combination.

Not Provided
Interventional
Phase 1
Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Locally Advanced Solid Tumor
  • Metastatic Solid Tumor
  • Breast Cancer
  • Non Small Cell Lung Cancer
  • Melanoma
  • Colorectal Cancer
  • Drug: MSC1936369B (pimasertib)
    MSC1936369B (pimasertib) will be administered orally 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 subjects with Breast Cancer, Non-Small Cell Lung Cancer (NSCLC), Melanoma, and Colorectal Cancer.
    Other Name: Pimasertib
  • Drug: SAR245409 (PI3K and mTOR inhibitor)
    SAR245409 (PI3K and mTOR inhibitor) will be administered orally in successive 21-day cycles. Dose escalation will proceed until 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 subjects with Breast Cancer, NSCLC, Melanoma, and Colorectal Cancer.
    Other Name: PI3K and mTOR inhibitor
  • Drug: MSC1936369B (pimasertib)
    MSC1936369B (pimasertib) will be administered orally in successive 21-day cycles. Dose escalation will proceed until MTD is reached. The maximum tolerated dose of MSC1936369B (pimasertib) will be combined with a lower dose of SAR245409 (PI3K and mTOR inhibitor).
    Other Name: pimasertib
  • Drug: SAR245409 (PI3K and mTOR inhibitor)
    SAR245409 (PI3K and mTOR inhibitor) will be administered orally in successive 21-day cycles. Dose escalation will proceed until MTD is reached. The maximum tolerated dose of SAR245409 (PI3K and mTOR inhibitor) will be combined with a lower dose of MSC1936369B (pimasertib).
    Other Name: PI3K and mTOR inhibitor
  • Experimental: MSC1936369B and SAR245409 once daily
    Interventions:
    • Drug: MSC1936369B (pimasertib)
    • Drug: SAR245409 (PI3K and mTOR inhibitor)
  • Experimental: MSC1936369B and SAR245409 twice daily
    Interventions:
    • Drug: MSC1936369B (pimasertib)
    • Drug: SAR245409 (PI3K and mTOR inhibitor)
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
259
May 2014
May 2014   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • 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
  • Subject with archived tumor tissue available for transfer to the Sponsor
  • 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
  • Subject has measurable or evaluable disease by RECIST v1.1
  • Subject is aged >= 18 years
  • 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
  • Other protocol-defined inclusion criteria could apply

Exclusion Criteria:

  • Subject has been previously treated with a PI3K inhibitor or a MEK inhibitor and taken off treatment due to treatment related adverse events
  • 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
  • Extensive prior radiotherapy on more than 30% bone marrow reserves, or prior bone marrow/stem cell transplantation
  • Subject has not recovered from toxicity due to prior therapy
  • Subject has poor organ and marrow function as defined in the protocol
  • Subject has a history of central nervous system metastases, unless subject has been previously treated for CNS metastases
  • Subject has a history of difficulty swallowing, malabsorption or other chronic gastrointestinal disease
  • Subject has a history of recent major surgery or trauma within the last 28 days.
  • Subject has participated in another clinical trial within the past 30 days
  • Other protocol-defined exclusion criteria could apply
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States,   Italy,   Spain
 
NCT01390818
EMR 200066-006
Yes
EMD Serono
EMD Serono
Sanofi
Study Director: Medical Responsible EMD Serono, an affiliate of MerckKGaA, Darmstadt, Germany
EMD Serono
July 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP