Combination Trial of Pimasertib (MSC1936369B) With Temsirolimus

Study Overview
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Brief Summary
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The research trial is testing the experimental drug pimasertib and the drug Torisel, given together, in the treatment of advanced solid tumors. The primary purpose of the study is to determine the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) of the drug combination.

Official Title
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Phase I Dose Escalation Trial of MEK1/2 Inhibitor MSC1936369B Combined With Temsirolimus in Subjects With Advanced Solid Tumors

Conditions
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Advanced Solid Tumor

Intervention / Treatment
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* Drug: Pimasertib
* Drug: Pimasertib
* Drug: Temsirolimus
* Drug: Temsirolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with histologically or cytologically confirmed solid tumors, either refractory to standard therapy or for which no effective standard therapy is available. Measurable or evaluable disease at baseline by RECIST 1.0. Age >= 18 years. Subject has read and understands the informed consent form and is willing and able to give informed consent. Performance Status score of less than or equal to (<=) 1 according to the Eastern Cooperative Oncology Group (ECOG) scale. Women of childbearing potential must have a negative blood pregnancy test at the screening visit. Female subjects of childbearing potential and male subjects with female partners of childbearing potential must be willing to avoid pregnancy by using an adequate method of contraception for 2 weeks prior to screening, during the trial and for 3 months after the last dose of trial medication. Additional inclusion criteria also apply. Exclusion Criteria: The subject has previously been treated with mammalian target of rapamycin (mTOR) inhibitor or a mitogen-activated protein kinase (MEK) inhibitor and taken off treatment due to drug-related AEs. The subject has received any of the following: Chemotherapy, immunotherapy, hormonal therapy, biologic therapy, any investigational agent or any other anti-cancer therapy within 28 days (6 weeks for nitrosoureas or mitomycin C) of Day 1 of trial treatment; non-cytotoxic chemotherapy or investigational agent with limited potential for delayed toxicity is permitted if terminated at least 5 half-lives prior to Day 1 of trial treatment. Extensive prior radiotherapy on more than 30% of bone marrow reserves, or prior bone marrow/stem cell transplantation. The subject has not recovered from toxicity due to prior therapy to baseline or CTCAE v4.0 of Grade 1 or less (except alopecia). The subject has poor organ or marrow function as defined in protocol. History of central nervous system (CNS) metastases or primary CNS tumor, unless subject has been previously treated for these conditions, is asymptomatic and has had no requirement for anticonvulsants or high dose corticosteroids for a minimum of 2 weeks prior to entry into the trial. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months of Day 1 of trial drug treatment. Recent major surgery or trauma (within the last 28 days), unhealing/open wounds, diabetic ulcers, recent drainage of significant volume of ascites or pleural effusion. History of congestive heart failure, unstable angina, myocardial infarction, symptomatic cardiac conduction abnormality, pacemaker, or other clinically significant cardiac disease or history of a stroke within 3 months prior to entering the trial. Baseline corrected QT interval on screening electrocardiogram (ECG) (QTc) >= 460 ms or left ventricular ejection fraction (LVEF) < 40% on screening echocardiogram. Other uncontrolled intercurrent diseases Retinal degenerative disease (hereditary retinal degeneration or age-related macular degeneration), history of uveitis or history of retinal vein occlusion, or medically relevant abnormal ophthalmology assessments at screening. Known or suspected allergy to pimasertib, temsirolimus, other rapamycins (sirolimus, everolimus, etc.), their excipients, or any agent given in the course of this trial. Immunization with attenuated live vaccines within one week of trial entry (examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG, etc.). Concomitant use of any medications or substances that are strong inhibitors or inducers of CYP3A enzyme, including, but not limited to, phenytoin, carbamazepine, barbiturates, azoles, rifampin, phenobarbital, or St. John's Wort. Pregnant or lactating female. Legal incapacity or limited legal capacity. Additional exclusion criteria also apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pimasertib 45 mg+Temsirolimus 12.5 mg<br> | Drug: Pimasertib<br>* Pimasertib will be administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Treatment will be continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.<br>* Other names: MSC1936369B;Drug: Temsirolimus<br>* Temsirolimus will be administered at a dose of 12.5 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment will be continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.<br>|
| Experimental: Pimasertib 45 mg+Temsirolimus 25 mg<br> | Drug: Pimasertib<br>* Pimasertib will be administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Treatment will be continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.<br>* Other names: MSC1936369B;Drug: Temsirolimus<br>* Temsirolimus will be administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment will be continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.<br>|
| Experimental: Pimasertib 75 mg+Temsirolimus 25 mg<br> | Drug: Pimasertib<br>* Pimasertib will be administered in fasted state at a dose of 75 mg once daily orally on Days 1 to 15. Treatment will be continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.<br>* Other names: MSC1936369B;Drug: Temsirolimus<br>* Temsirolimus will be administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment will be continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Dose Limiting Toxicities (DLTs) | DLT was defined as any of the following toxicities graded as per National Cancer Institute (NCI) common terminology criteria for adverse events (NCI CTCAE v4.0) encountered within cycle 1 of treatment at any dose level and judged not to be related to the underlying disease or concomitant medications. A treatment emergent adverse event (TEAE) of potential clinical significance such that further dose escalation would expose subjects to unacceptable risk; any Grade >=3 non-hematological toxicity except Grade 3 asymptomatic increases in liver function tests, diarrhea, nausea or vomiting with duration <= 48 hours and alopecia; Grade 4 neutropenia of >5 days duration or febrile neutropenia of >1 day duration; Grade 3 thrombocytopenia with bleeding or Grade 4 thrombocytopenia; any treatment interruption >2 weeks due to adverse events; any severe, impairing daily functions or life-threatening, complication or abnormality not defined in NCI-CTCAE that is attributable to the therapy. | Up to 21 Days (within Cycle 1) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Treatment-emergent Adverse Events (TEAEs) | An AE was defined as any new untoward medical occurrences/worsening of pre-existing medical condition, whether or not related to study drug. The TEAEs were those events that occur between first dose of trial treatment and up to 30 days after last dose of the trial treatment that were absent before treatment or that worsened relative to pretreatment state. | From the start of the trial treatment until data cut-off date (23 February 2012) | 
| Maximum Plasma Concentration (Cmax) of Pimasertib | Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan. | Drug-drug interaction (DDI) cohorts: Days 1 and 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1 | 
| Maximum Plasma Concentration (Cmax) of Temsirolimus | Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan. | DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 8 | 
| Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib | Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan. | DDI cohorts: Days 1 and 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1 | 
| Time to Reach Maximum Plasma Concentration (Tmax) of Temsirolimus | Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan. | DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1 | 
| Area Under the Concentration Time Curve During a Dosing Interval (AUCtau) and Area Under the Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib | The AUCtau was defined as the area under the concentration curve divided by the dosing interval. AUC(0-inf) was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan. | DDI cohorts: Days 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1 for AUCtau; DDI cohorts: Day 1 of Cycle 1 AUC0-inf | 
| Area Under Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Temsirolimus | The AUC(0-inf) was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan. | DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1 | 
| Apparent Terminal Half-life (t1/2) of Pimasertib | The t1/2 was defined as the time required for the plasma concentration of drug to decrease 50% in the final stage of its elimination. Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan. | DDI cohorts: Days 1 and 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1 | 
| Apparent Terminal Half-life (t1/2) of Temsirolimus | The t1/2 was defined as the time required for the plasma concentration of drug to decrease 50% in the final stage of its elimination. Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan. | DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1 | 
| Apparent Clearance From Plasma Following Oral Administration (CL/f) of Pimasertib | Clearance (CL) of a drug was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. The CL obtained after oral dose (CL/F) was influenced by the fraction of the dose absorbed (bioavailability). Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan. | DDI cohorts: Days 1 and 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1 | 
| Total Body Clearance From Plasma Following Intravenous Administration (CL) of Temsirolimus | The clearance of a drug was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan. | DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1 | 
| Apparent Volume of Distribution (Vz/F) of Pimasertib | Volume of distribution (Vz) was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. The Vz after oral dose (Vz/F) was influenced by the fraction absorbed. Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan. | DDI cohorts: Days 1 and 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1 | 
| Volume of Distribution (Vz) of Temsirolimus | The Vz was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan. | DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1 | 
| Number of Subjects With Disease Control Rate | Disease control is defined as confirmed complete response (CR), partial response (PR), or stable disease (SD) >=12 weeks), based on tumor assessments as determined by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0. CR: The disappearance of all lesions and normalization of tumor marker level. PR: At least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the sum of the longest diameter at baseline. SD: Neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum of the longest diameter since treatment started. | From the start of the trial treatment until data cut-off date (23 February 2012) | 
| Phospho Extracellular Signal Regulated Kinase (pERK ) Levels and Phospho Ribosomal Protein S6 (pS6) Levels in in Peripheral Blood Mononuclear Cells (PBMCs) | During the first cycle (either Cycle 1 non-DDI or Cycle 1-DDI) blood samples will be collected for pharmacodynamic marker assessments by flow cytometry such as phospho-ERK and phospho- S6 activities in PBMCs | DDI cohorts: Days 1, 9 and 10 of Cycle 1; Non-DDI cohorts: Days 1, 8 and 9 of Cycle 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MEK inhibitor, Temsirolimus, Neoplasms, Phase I, Pimasertib