Relative Bioavailability of Pimasertib in Cancer Patients

Study Overview
=================
Brief Summary
-----------------
This is a Phase 1, multi-center, open-label, single-dose, 2 period, 2 sequence cross-over trial to investigate the relative bioavailability of 2 solid oral pimasertib formulations in cancer subjects (Part A), followed by open-label pimasertib administration (Part B and trial extension phase).

Official Title
-----------------
A Multi-Center, Open-Label, Single 60 mg Dose, Two Period, Two Sequence Cross-Over Trial to Investigate the Relative Bioavailability of Two Solid Oral Pimasertib Formulations in Cancer Patients

Conditions
-----------------
Neoplasms

Intervention / Treatment
-----------------
* Drug: Pimasertib Capsule (Part A)
* Drug: Pimasertib Tablet (Part A)
* Drug: Pimasertib Tablet (Part A)
* Drug: Pimasertib Capsule (Part A)
* Drug: Pimasertib Capsule (Part B and trial extension phase)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Pathologically confirmed solid tumors, either refractory to standard therapy or for which no effective standard therapy is available, with a measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 An Eastern Cooperative Oncology Group Performance Status (ECOG PS) of less than or equal to (<=) 1 Other protocol defined inclusion criteria could apply Exclusion Criteria: Disease conditions or concomitant medication that may significantly influence the conduct of the trial or an abnormal electrocardiogram (ECG) or blood pressure at Screening as defined in the protocol Treatment with strong inhibitors or inducers of cytochrome P450 2C19 (CYP2C19) and CYP3A4 including fruit juices or beverages containing these substances History of prior mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) kinase (MEK) inhibitor exposure (including, pimasertib) or progression of disease on MEK inhibitors Evidence of a retinal vein occlusion (RVO) on fluorescein angiogram or a history of RVO Life expectancy of less than 12 weeks Other protocol defined exclusion criteria could apply

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pimasertib Capsule/Pimasertib Tablet<br> | Drug: Pimasertib Capsule (Part A)<br>* Pimasertib capsule administration at a single dose of 60 milligram (mg) orally on Day 1 in Part A.<br>* Other names: MSC1936369B;Drug: Pimasertib Tablet (Part A)<br>* Pimasertib tablet administration at a single dose of 60 mg orally on Day 3 in Part A.<br>* Other names: MSC1936369B;Drug: Pimasertib Capsule (Part B and trial extension phase)<br>* Subjects completing Part A to receive pimasertib capsule at a dose of 60 mg orally twice daily in cycles of 21 days each in Part B and trial extension phase until disease progression, intolerable toxicity, subject withdrawal, loss to follow-up or death.<br>* Other names: MSC1936369B;|
| Experimental: Pimasertib Tablet/Pimasertib Capsule<br> | Drug: Pimasertib Tablet (Part A)<br>* Pimasertib tablet administration at a single dose of 60 mg orally on Day 1 in Part A.<br>* Other names: MSC1936369B;Drug: Pimasertib Capsule (Part A)<br>* Pimasertib capsule administration at a single dose of 60 mg orally on Day 3 in Part A.<br>* Other names: MSC1936369B;Drug: Pimasertib Capsule (Part B and trial extension phase)<br>* Subjects completing Part A to receive pimasertib capsule at a dose of 60 mg orally twice daily in cycles of 21 days each in Part B and trial extension phase until disease progression, intolerable toxicity, subject withdrawal, loss to follow-up or death.<br>* Other names: MSC1936369B;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) | Maximum observed plasma concentration (Cmax) was calculated for Part A Pimasertib 60 mg Capsule and tablet. | Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 4, 8, and 24 hours post-dose on Day 1 and 3 | 
| Area Under the Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration (AUC 0-t) | Area under the plasma concentration-time curve from time zero to the last sampling time (AUC0-t) at which the concentration was at or above the lower limit of quantification. | Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 4, 8, and 24 hours post-dose on Day 1 and 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC0-inf) |  | Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 4, 8, and 24 hours post-dose on Day 1 and 3 | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) |  | Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 4, 8, and 24 hours post-dose on Day 1 and 3 | 
| Apparent Terminal Half-life (t1/2) |  | Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 4, 8, and 24 hours post-dose on Day 1 and 3 | 
| Apparent Total Body Clearance (CL/f) | Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. | Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 4, 8, and 24 hours post-dose on Day 1 and 3 | 
| Apparent Volume of Distribution (Vz/f) | 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) is influenced by the fraction absorbed. | Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 4, 8, and 24 hours post-dose on Day 1 and 3 | 
| Terminal Rate Constant (λz) |  | Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 4, 8, and 24 hours post-dose on Day 1 and 3 | 
| Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation | An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug administration until 30 days after the last dose of study drug administration that were absent before treatment or that worsened relative to pre treatment state. | From the first dose of study drug administration until 30 days after the last dose of study drug administration, assessed up to 14 Months | 
| Part B: Number of Subjects Who Experienced Complete Response (CR) | CR as per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 defined as disappearance of all target lesions except lymph nodes (LN); LN must have a decrease in the short axis to less than (<)10 millimeter (mm). | Screening to Day 1 of each cycle (21 day in each cycle) until disease progression, intolerable toxicity, withdrawal of consent or death; assessed up to 14 Months | 
| Part B: Number of Subjects Who Experienced Partial Response (PR) | PR as per RECIST v1.1 defined as 30% decrease in sum of diameters of target lesions taking as reference the baseline sum diameters. | Screening to Day 1 of each cycle (21 day in each cycle) until disease progression, intolerable toxicity, withdrawal of consent or death; assessed up to 14 Months | 
| Part B: Number of Subjects Who Experienced Stable Disease (SD) | SD as per RECIST v1.1 defined as neither shrinkage to qualify for PR nor increase to qualify for progressive disease (PD) taking the smallest sum diameters on study as reference. PR = 30% decrease in sum of diameters of target lesions taking as reference the baseline sum diameters; PD = 20% increase in sum of diameters of target lesions; the appearance of >=1 new lesions. | Screening to Day 1 of each cycle (21 day in each cycle) until disease progression, intolerable toxicity, withdrawal of consent or death; assessed up to 14 Months | 
| Part B: Number of Subjects Who Experienced Progressive Disease (PD) | PD as per RECIST v1.1 defined as 20% increase in sum of diameters of target lesions; the appearance of >=1 new lesions. | Screening to Day 1 of each cycle (21 day in each cycle) until disease progression, intolerable toxicity, withdrawal of consent or death; assessed up to 14 Months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Neoplasms, Pimasertib, Cancer