NCT01390818 · REGISTRY CONDITION SEARCH

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

Found through the registry condition index, not selected as a treatment recommendation. This discovery collection was restricted to studies with posted results.

Phase: PHASE1
Status at capture: COMPLETED
Registry last update: 2017-03-07

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.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Number of Subjects With Dose Limiting Toxicities (DLT)

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outcome · POSTED

Number of Subjects Experiencing Any Treatment-Emergent Adverse Events (TEAEs)

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outcome · POSTED

Maximum Observed Plasma Concentration (Cmax) for Pimasertib (MSC1936369B)

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outcome · POSTED

Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib (MSC1936369B)

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outcome · POSTED

Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of Pimasertib (MSC1936369B)

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outcome · POSTED

Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC 0-inf) of Pimasertib (MSC1936369B) at Day 1

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outcome · POSTED

Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of Pimasertib (MSC1936369B)

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outcome · POSTED

Half-Life (t1/2) of MSC1936369B (Pimasertib)

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outcome · POSTED

Total Body Clearance (CL/f) of Pimasertib (MSC1936369B)

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outcome · POSTED

Apparent Volume of Distribution of Total Pimasertib During the Terminal Phase Following Oral Administration (Vz/f) of Pimasertib

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outcome · POSTED

Accumulation Ratio (Racc) for AUCtau of Pimasertib (MSC1936369B): Day 15

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outcome · POSTED

Accumulation Ratio (Racc) for Cmax of Pimasertib (MSC1936369B): Day 15

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outcome · POSTED

Maximum Observed Plasma Concentration (Cmax) for SAR245409

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outcome · POSTED

Time to Reach Maximum Plasma Concentration (Tmax) of SAR245409

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outcome · POSTED

Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of SAR245409

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outcome · POSTED

Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of SAR245409

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outcome · POSTED

Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to Infinity (0-inf) of SAR245409: Day 1

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outcome · POSTED

Apparent Terminal Half-Life (t1/2) of SAR245409

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outcome · POSTED

Total Body Clearance (CL/f) of SAR245409

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outcome · POSTED

Apparent Volume of Distribution of Total SAR245409 During the Terminal Phase Following Oral Administration (Vz/f)

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outcome · POSTED

Accumulation Ratio (Racc) for AUCtau of SAR245409: Day 15

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outcome · POSTED

Accumulation Ratio (Racc) for Cmax of SAR245409: Day 15

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outcome · POSTED

pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)

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outcome · POSTED

pERK Concentrations in PBMCs

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outcome · POSTED

Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part

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
healthy Volunteers: false
maximum Age: 82 Years
minimum Age: 18 Years
sex: ALL
std Ages: ADULT
OLDER_ADULT

Treatment arms and interventions

arm Groups

intervention Names
Drug: MSC1936369B (pimasertib)
Drug: SAR245409 (PI3K and mTOR inhibitor)
label
MSC1936369B and SAR245409 once daily
type
EXPERIMENTAL
intervention Names
Drug: MSC1936369B (pimasertib)
Drug: SAR245409 (PI3K and mTOR inhibitor)
label
MSC1936369B and SAR245409 twice daily
type
EXPERIMENTAL

interventions

arm Group Labels
MSC1936369B and SAR245409 once daily
description
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.
name
MSC1936369B (pimasertib)
other Names
Pimasertib
type
DRUG
arm Group Labels
MSC1936369B and SAR245409 once daily
description
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.
name
SAR245409 (PI3K and mTOR inhibitor)
other Names
PI3K and mTOR inhibitor
type
DRUG
arm Group Labels
MSC1936369B and SAR245409 twice daily
description
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).
name
MSC1936369B (pimasertib)
other Names
pimasertib
type
DRUG
arm Group Labels
MSC1936369B and SAR245409 twice daily
description
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).
name
SAR245409 (PI3K and mTOR inhibitor)
other Names
PI3K and mTOR inhibitor
type
DRUG

Study design

allocation

NON_RANDOMIZED

intervention Model

SINGLE_GROUP

masking Info

masking: NONE

primary Purpose

TREATMENT

Enrollment

count: 146
type: ACTUAL

Registered outcome plans (not posted results)

primary Outcomes

description
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.
measure
Number of Subjects With Dose Limiting Toxicities (DLT)
time Frame
Day 1 up to Day 16 in cycle 1

secondary Outcomes

description
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.
measure
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
measure
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
measure
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
description
Area under the concentration-time curve from time 0 to the last quantifiable concentration.
measure
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
description
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).
measure
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
measure
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
measure
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
description
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.
measure
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
description
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.
measure
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
description
Accumulation ratio (Racc) for AUCtau, calculated as Day 15 dosing interval AUCtau per Day 1 dosing interval AUCtau.
measure
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
description
Accumulation ratio (Racc) for Cmax, calculated as Day 15 Cmax/Day 1 Cmax.
measure
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
measure
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

Full study description

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.

Source references

Source notices and limitations

Discovery and provenance

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NCT01390818
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Preserved source evidence · Not medical advice