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

Phase 1

Completed

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

Interventions: Drug: MSC1936369B (pimasertib)
Drug: SAR245409 (PI3K and mTOR inhibitor)

Registration Number: NCT01390818

Lead Sponsor: EMD Serono

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 available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 146

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
MSC1936369B and SAR245409 once daily	MSC1936369B (pimasertib)	-
MSC1936369B and SAR245409 twice daily	MSC1936369B (pimasertib)	-
MSC1936369B and SAR245409 once daily	SAR245409 (PI3K and mTOR inhibitor)	-
MSC1936369B and SAR245409 twice daily	SAR245409 (PI3K and mTOR inhibitor)	-

Primary Outcome Measures

Name	Time	Method
Number of Subjects With Dose Limiting Toxicities (DLT)	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.

Secondary Outcome Measures

Name	Time	Method
Number of Subjects Experiencing Any Treatment-Emergent Adverse Events (TEAEs)	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.
Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC 0-inf) of Pimasertib (MSC1936369B) at Day 1	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).
Half-Life (t1/2) of MSC1936369B (Pimasertib)	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
Maximum Observed Plasma Concentration (Cmax) for Pimasertib (MSC1936369B)	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	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 Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of SAR245409	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	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	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)	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)	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 Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of Pimasertib (MSC1936369B)	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)	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.
Total Body Clearance (CL/f) of SAR245409	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)	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.
pERK Concentrations in PBMCs	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.
Apparent Volume of Distribution of Total Pimasertib During the Terminal Phase Following Oral Administration (Vz/f) of Pimasertib	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	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	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	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 of SAR245409: Day 15	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.
Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	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.
Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of SAR245409	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).
Accumulation Ratio (Racc) for Cmax of SAR245409: Day 15	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)	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.

Trial Locations

Locations (7): Memorial Sloan Kettering Cancer Center
🇺🇸
New York, New York, United States
Cedars Sinai Medical Center
🇺🇸
Los Angeles, California, United States
Cancer Therapy and Research Center
🇺🇸
San Antonio, Texas, United States
Merck Serono Research Site
🇪🇸
Madrid, Spain
Massachusetts General Hospital
🇺🇸
Boston, Massachusetts, United States
Sarah Cannon Research Institute
🇺🇸
Nashville, Tennessee, United States
Pinnacle Oncology Hematology
🇺🇸
Scottsdale, Arizona, United States