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

• ClinicalTrials.gov Identifier: NCT01390818
• Recruitment Status: Completed
• First Posted: July 11, 2011
• Results First Posted: March 7, 2017
• Last Update Posted: March 7, 2017
• Sponsor: EMD Serono
• Collaborator: Sanofi
• Information provided by (Responsible Party): EMD Serono

Tracking Information

• First Submitted Date: April 18, 2011
• First Posted Date: July 11, 2011
• Results First Submitted Date: May 1, 2016
• Results First Posted Date: March 7, 2017
• Last Update Posted Date: March 7, 2017
• Study Start Date: May 2011
• Actual Primary Completion Date: April 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 17, 2017)

Number of Subjects With Dose Limiting Toxicities (DLT) [ Time Frame: Day 1 up to Day 16 in cycle 1 ]

DLT was defined as any of the following toxicities experienced during the first cycle of treatment at any dose level (DL) and judged not to be related to the underlying disease or any concomitant medication by the Investigator and/or the Sponsor: A treatment emergent adverse event (TEAE) of potential clinical significance such that further dose escalation (DE) would have exposed subjects to unacceptable risk. Any Grade greater than or equal to (>=) 3 non-hematological toxicity, except for: Grade 3 diarrhea, nausea and vomiting with a duration less than or equal to (<=) 48 hours despite adequate supportive care and Alopecia. Grade 4 neutropenia of > 5 days duration or febrile neutropenia. Grade 3 thrombocytopenia with bleeding or Grade 4 thrombocytopenia. Any treatment interruption > 2 weeks due to AEs not related to the underlying disease or concomitant medication at any dose level and any severe, life-threatening impairing daily functions complication or abnormality.

Original Primary Outcome Measures (submitted: July 8, 2011)

The number and proportion of subjects with dose limiting toxicities [ Time Frame: 22 months ]

This will be used as the primary measure for determining the Maximum Tolerated Dose (MTD) of MSC1936369B and SAR245409 combination therapy.

Current Secondary Outcome Measures (submitted: January 17, 2017)

• Number of Subjects Experiencing Any Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: Baseline up to 30 Days after last dose; assessed up to 4 years ]
  An adverse event (AE) was defined as any untoward medical occurrence in a subject administered a pharmaceutical product, which did not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAEs were defined as those AEs that started between first dose of study drug and up to 30 days after last dose.
• Maximum Observed Plasma Concentration (Cmax) for Pimasertib (MSC1936369B) [ Time Frame: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts ]
• Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib (MSC1936369B) [ Time Frame: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts ]
• Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of Pimasertib (MSC1936369B) [ Time Frame: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts ]
  Area under the concentration-time curve from time 0 to the last quantifiable concentration.
• Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC 0-inf) of Pimasertib (MSC1936369B) at Day 1 [ Time Frame: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1 for DE cohorts ]
  Area under the concentration-time curve from time 0 extrapolated to infinity, calculated as AUC0-t + last observed concentration (Clast)/terminal rate constant (λz), using the Linear up/Log down method. Terminal rate constant (λz).
• Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of Pimasertib (MSC1936369B) [ Time Frame: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts ]
• Half-Life (t1/2) of MSC1936369B (Pimasertib) [ Time Frame: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts ]
• Total Body Clearance (CL/f) of Pimasertib (MSC1936369B) [ Time Frame: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts ]
  The total body clearance of drug from plasma following oral administration (Cl/f) and the total body clearance of drug from plasma following intravenous administration was calculated by dividing the Dose with area under the plasma concentration time curve from time zero to infinity (AUC0 inf)=Dose/AUC0- inf.
• Apparent Volume of Distribution of Total Pimasertib During the Terminal Phase Following Oral Administration (Vz/f) of Pimasertib [ Time Frame: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts ]
  Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/f) was influenced by the fraction absorbed. Apparent volume of distribution during the terminal phase, calculated by CL/f/λz. Terminal rate constant (λz). The regression analysis (determination of λz) was to contain as many data points as possible (but excluding Cmax) and had to include concentration data from at least 3 different time points, consistent with the assessment of a straight line (the terminal elimination phase) on the log-transformed scale.Data was not available for 'Pimasertib (MSC1936369B) 60mg Twice Daily' arm as no subjects were considered evaluable because of limited number of samples collected to characterize the terminal phase rate constant needed for the calculation of Vz/f.
• Accumulation Ratio (Racc) for AUCtau of Pimasertib (MSC1936369B): Day 15 [ Time Frame: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts ]
  Accumulation ratio (Racc) for AUCtau, calculated as Day 15 dosing interval AUCtau per Day 1 dosing interval AUCtau.
• Accumulation Ratio (Racc) for Cmax of Pimasertib (MSC1936369B): Day 15 [ Time Frame: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts ]
  Accumulation ratio (Racc) for Cmax, calculated as Day 15 Cmax/Day 1 Cmax.
• Maximum Observed Plasma Concentration (Cmax) for SAR245409 [ Time Frame: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts ]
• Time to Reach Maximum Plasma Concentration (Tmax) of SAR245409 [ Time Frame: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts ]
  The time to reach maximum plasma concentration (Tmax) of SAR245409 was calculated.
• Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of SAR245409 [ Time Frame: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts ]
  Area under the plasma concentration-time curve (AUC) from time zero to the last sampling time (0-24 hours) at which the concentration is at or above the lower limit of quantification. Unit of assessment was hour*nanogram per milliliter (hr*ng/mL).
• Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of SAR245409 [ Time Frame: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts ]
• Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to Infinity (0-inf) of SAR245409: Day 1 [ Time Frame: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1 for DE cohorts ]
  Area under the concentration-time curve from time 0 extrapolated to infinity, calculated as AUC0-t + last observed concentration (Clast)/terminal rate constant (λz), using the Linear up/Log down method. Terminal rate constant (λz). The regression analysis (determination of λz) was to contain as many data points as possible (but excluding Cmax) and had to include concentration data from at least 3 different time points, consistent with the assessment of a straight line (the terminal elimination phase) on the log-transformed scale.
• Apparent Terminal Half-Life (t1/2) of SAR245409 [ Time Frame: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts ]
• Total Body Clearance (CL/f) of SAR245409 [ Time Frame: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts ]
  The total body clearance of drug from plasma following oral administration (Cl/f) and the total body clearance of drug from plasma following intravenous administration was calculated by dividing the dose with area under the plasma concentration time curve from time zero to infinity (AUC 0-inf)=Dose/AUC 0-inf.
• Apparent Volume of Distribution of Total SAR245409 During the Terminal Phase Following Oral Administration (Vz/f) [ Time Frame: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts ]
  Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/f) was influenced by the fraction absorbed. Apparent volume of distribution during the terminal phase, calculated by CL/f/λz. Terminal rate constant (λz). The regression analysis (determination of λz) was to contain as many data points as possible (but excluding Cmax) and had to include concentration data from at least 3 different time points, consistent with the assessment of a straight line (the terminal elimination phase) on the log-transformed scale.
• Accumulation Ratio (Racc) for AUCtau of SAR245409: Day 15 [ Time Frame: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts ]
  Accumulation ratio (Racc) for AUCtau, calculated as Day 15 dosing interval AUCtau divided by Day 1 dosing interval AUCtau.
• Accumulation Ratio (Racc) for Cmax of SAR245409: Day 15 [ Time Frame: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts ]
  Accumulation ratio (Racc) for Cmax, calculated as Day 15 Cmax divided by Day 1 Cmax.
• pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs) [ Time Frame: DDI Evaluation: Day 1 and 3 (predose, 2, 4, 8 and 24 hours (hr) postdose); Day 2 and 4 (24 hr postdose); Cycle 1 Day 1 (C1D1) and C1D15 (predose, 2, 4, 8, 24 hr postdose); C1D2 and C1D16 (24 hr postdose); C1D19 (predose, 2 hr postdose) ]
  pS6 Concentrations in PBMCs was measured during DDI Evaluation period and Cycle 1 for DE cohorts. DDI evaluation period is a 4-day period that was performed within 1 week prior to Day 1 Cycle 1. In DDI evaluation period, On Day 1, SAR245409 was be administered alone, and on Day 3, Pimasertib was administered alone. No data were planned to be collected for "Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily", "Pimasertib (MSC1936369B) 45mg and SAR245409 50mg Twice Daily", "Pimasertib (MSC1936369) 30mg and SAR245409 70mg Once Daily" and "Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily" reporting arms.
• pERK Concentrations in PBMCs [ Time Frame: DDI Evaluation: Day 1 and 3 (predose, 2, 4, 8 and 24 hours (hr) postdose); Day 2 and 4 (24 hr postdose); C1D1 and C1D15 (predose, 2, 4, 8, 24 hr postdose); C1D2 and C1D16 (24 hr postdose); C1D19 (predose, 2 hr postdose) ]
  pERK Concentrations in PBMCs was measured during DDI Evaluation period and Cycle 1 for DE cohorts. DDI evaluation period is a 4-day period that was performed within 1 week prior to Day 1 Cycle 1. In DDI evaluation period, On Day 1, SAR245409 was be administered alone, and on Day 3, Pimasertib was administered alone. No data were planned to be collected for "Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily", "Pimasertib (MSC1936369B) 45mg and SAR245409 50mg Twice Daily", "Pimasertib (MSC1936369) 30mg and SAR245409 70mg Once Daily" and "Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily" reporting arms.
• Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD) [ Time Frame: From the date of randomisation every 6 weeks up to assessed up to 4 years ]
  CR=Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<) 10 millimeter (mm). PR=At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD=Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study. PD= At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Original Secondary Outcome Measures (submitted: July 8, 2011)

• Number of participants experiencing any treatment-emergent adverse event [ Time Frame: 22 months ]
• Cmax of MSC1936369B in subjects with advanced or metastatic solid tumors [ Time Frame: 22 months ]
  Plasma pharmacokinetic (PK) parameter: Maximum concentration (Cmax)
• AUC of MSC1936369B in subjects with advanced or metastatic solid tumors [ Time Frame: 22 months ]
  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 ]
  Plasma pharmacokinetic parameter: Time to reach maximum concentration (Tmax)
• Cmax of SAR245409 in subjects with advanced or metastatic solid tumors [ Time Frame: 22 months ]
  Plasma pharmacokinetic parameter
• AUC of SAR245409 in subjects with advanced or metastatic solid tumors [ Time Frame: 22 months ]
  Plasma pharmacokinetic parameter
• Tmax of SAR245409 in subjects with advanced or metastatic solid tumors [ Time Frame: 22 months ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  Pharmacodynamic marker
• pERK concentrations in PBMCs [ Time Frame: 22 months ]
  Pharmacodynamic marker
• Number and proportion of subjects with complete tumor response, partial tumor response, or stable disease. [ Time Frame: 22 months ]
  Clinical benefit based on the Investigator tumor evaluations performed every 6 weeks in accordance with Response Evaluation Criteria In Solid Tumors (RECIST) v1.1

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Trial of MEK Inhibitor and PI3K/mTOR Inhibitor in Subjects With Locally Advanced or Metastatic Solid Tumors
• 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
• Brief Summary: 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Locally Advanced Solid Tumor
• Metastatic Solid Tumor
• Breast Cancer
• Non Small Cell Lung Cancer
• Melanoma
• Colorectal Cancer

Intervention

• Drug: MSC1936369B (pimasertib)
  MSC1936369B (pimasertib) single dose capsule was administered at dose of 15 milligram (mg), 30 mg, 60 mg, 90 mg orally in successive 21-day cycles.Dose escalation was proceeded until Maximum Tolerated Dose (MTD) was reached. Once the MTD was reached, enrollment began in four disease-specific expansion cohorts at either the MTD or a lower dose recommended by the Safety Monitoring Committee. The four expansion cohorts enrolled 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) capsule was administered orally at a dose of 30 mg, 50 mg, 70 mg and 90 mg in successive 21-day cycles. Dose escalation was proceeded until MTD was reached. Once the MTD was reached, enrollment began in four disease-specific expansion cohorts at either the MTD or a lower dose recommended by the Safety Monitoring Committee. The four expansion cohort enrolled subjects with Breast Cancer, NSCLC, Melanoma, and Colorectal Cancer.
  Other Name: PI3K and mTOR inhibitor
• Drug: MSC1936369B (pimasertib)
  MSC1936369B (pimasertib) capsule was administered twice daily orally at a dose of 60 mg and 45 mg in successive 21-day cycles. Dose escalation proceeded until MTD was reached. The maximum tolerated dose of MSC1936369B (pimasertib) was 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) was administered twice daily orally at a dose of 30 mg and 50 mg in successive 21-day cycles. Dose escalation proceeded until MTD was reached. The maximum tolerated dose of SAR245409 (PI3K and mTOR inhibitor) was combined with a lower dose of MSC1936369B (pimasertib).
  Other Name: PI3K and mTOR inhibitor

Study Arms

• 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)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 13, 2015): 146
• Original Estimated Enrollment (submitted: July 8, 2011): 90
• Actual Study Completion Date: April 2015
• Actual Primary Completion Date: April 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

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 response evaluation criteria in solid tumors (RECIST) v1.1
• Subject is aged greater than or equal to (>=) 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 Kirsten rat sarcoma viral oncogene homolog (KRAS) or neuroblastoma RAS viral oncogene homolog (NRAS) mutated metastatic non-small cell lung cancer (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 colorectal cancer (CRC) with dual KRAS and PIK3CA mutation with no approved therapies, or
  • BRAF V600E/K mutated unresectable or metastatic melanoma after progression on B-Raf proto-oncogene, serine/threonine kinase (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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 82 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Italy, Spain, United States

Administrative Information

• NCT Number: NCT01390818
• Other Study ID Numbers: EMR 200066-006
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: EMD Serono
• Study Sponsor: EMD Serono
• Collaborators: Sanofi

Investigators

• Study Director: Medical Responsible; EMD Serono, a business of Merck KGaA, Darmstadt, Germany

• PRS Account: EMD Serono
• Verification Date: January 2017