Neoplasms
Conditions
Keywords
Neoplasms, Pimasertib, Cancer
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).
Interventions
DRUGPimasertib Capsule (Part A)
Pimasertib capsule administration at a single dose of 60 milligram (mg) orally on Day 1 in Part A.
DRUGPimasertib Tablet (Part A)
Pimasertib tablet administration at a single dose of 60 mg orally on Day 3 in Part A.
DRUGPimasertib Capsule (Part B and trial extension phase)
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.
Sponsors
EMD Serono
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) | 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 | Maximum observed plasma concentration (Cmax) was calculated for Part A Pimasertib 60 mg Capsule and tablet. |
| Area Under the Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration (AUC 0-t) | 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 time zero to the last sampling time (AUC0-t) at which the concentration was at or above the lower limit of quantification. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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) | 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 | 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. |
| Apparent Volume of Distribution (Vz/f) | 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 | 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. |
| 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 | — |
| 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 | — |
| Part B: Number of Subjects Who Experienced Complete Response (CR) | 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 | 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). |
| Part B: Number of Subjects Who Experienced Partial Response (PR) | 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 | PR as per RECIST v1.1 defined as 30% decrease in sum of diameters of target lesions taking as reference the baseline sum diameters. |
| Part B: Number of Subjects Who Experienced Stable Disease (SD) | 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 | 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. |
| Part B: Number of Subjects Who Experienced Progressive Disease (PD) | 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 | PD as per RECIST v1.1 defined as 20% increase in sum of diameters of target lesions; the appearance of \>=1 new lesions. |
| Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation | From the first dose of study drug administration until 30 days after the last dose of study drug administration, assessed up to 14 Months | 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. |
| 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 | — |
Countries
United States
Participant flow
Recruitment details
First/last subject (informed consent): Nov 2013/Feb 2015. Clinical data cut-off: May 2014, Study completion date: Feb 2015
Pre-assignment details
A total of 45 subjects were screened. 38 subjects were enrolled and received the trial medication completed two sequence cross-over Part A and further continued in open label Part B.
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population It included all the subjects randomized to receive either Pimasertib 60 mg capsule and Pimasertib 60 mg tablet first in Part A and Pimasertib 60 mg capsule in Part B of the study. | 38 |
| Total | 38 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age, Continuous | 60.6 years STANDARD_DEVIATION 11.74 |
| Sex: Female, Male Female | 20 Participants |
| Sex: Female, Male Male | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 18 / 38 | 17 / 37 | 37 / 38 |
| serious Total, serious adverse events | 1 / 38 | 0 / 37 | 19 / 38 |
Outcome results
Primary
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.
Time frame: 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
Population: PK analysis set included all subjects who received the Part A IMP, had compliance with IMP intake in Part A, at least one post-treatment PK sample from each treatment period and absence of protocol deviations affecting bioavailability.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Pimasertib 60 mg Capsule | Area Under the Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration (AUC 0-t) | 979.0 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 76.5 |
| Part A: Pimasertib 60 mg Tablet | Area Under the Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration (AUC 0-t) | 1060.7 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 73 |
Primary
Maximum Observed Plasma Concentration (Cmax)
Maximum observed plasma concentration (Cmax) was calculated for Part A Pimasertib 60 mg Capsule and tablet.
Time frame: 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
Population: Pharmacokinetic (PK) analysis set included all subjects who received the Part A IMP, had compliance with IMP intake in Part A, at least one post-treatment PK sample from each treatment period and absence of protocol deviations affecting bioavailability.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Pimasertib 60 mg Capsule | Maximum Observed Plasma Concentration (Cmax) | 254.6 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 75.7 |
| Part A: Pimasertib 60 mg Tablet | Maximum Observed Plasma Concentration (Cmax) | 314.1 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 84.2 |
Secondary
Apparent Terminal Half-life (t1/2)
Time frame: 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
Population: PK analysis set included all subjects who received the Part A IMP, had compliance with IMP intake in Part A, at least one post-treatment PK sample from each treatment period and absence of protocol deviations affecting bioavailability. Here N (number of participants analyzed) signifies the number of subjects analysed for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Pimasertib 60 mg Capsule | Apparent Terminal Half-life (t1/2) | 4.38 hour |
| Part A: Pimasertib 60 mg Tablet | Apparent Terminal Half-life (t1/2) | 4.47 hour |
Secondary
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.
Time frame: 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
Population: PK analysis set included all subjects who received the Part A IMP, had compliance with IMP intake in Part A, at least one post-treatment PK sample from each treatment period and absence of protocol deviations affecting bioavailability. Here N (number of participants analyzed) signifies the number of subjects analysed for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Pimasertib 60 mg Capsule | Apparent Total Body Clearance (CL/f) | 54.041 liter per hour (L/h) | Geometric Coefficient of Variation 74.2 |
| Part A: Pimasertib 60 mg Tablet | Apparent Total Body Clearance (CL/f) | 54.092 liter per hour (L/h) | Geometric Coefficient of Variation 72.9 |
Secondary
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.
Time frame: 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
Population: PK analysis set included all subjects who received the Part A IMP, had compliance with IMP intake in Part A, at least one post-treatment PK sample from each treatment period and absence of protocol deviations affecting bioavailability. Here N (number of participants analyzed) signifies the number of subjects analysed for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Pimasertib 60 mg Capsule | Apparent Volume of Distribution (Vz/f) | 346.454 Liter | Geometric Coefficient of Variation 54.1 |
| Part A: Pimasertib 60 mg Tablet | Apparent Volume of Distribution (Vz/f) | 334.540 Liter | Geometric Coefficient of Variation 59 |
Secondary
Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC0-inf)
Time frame: 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
Population: PK analysis set included all subjects who received the Part A IMP, had compliance with IMP intake in Part A, at least one post-treatment PK sample from each treatment period and absence of protocol deviations affecting bioavailability. Here N (number of participants analysed) signifies the number of subjects analysed for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Pimasertib 60 mg Capsule | Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC0-inf) | 1110.3 h*ng/mL | Geometric Coefficient of Variation 74.2 |
| Part A: Pimasertib 60 mg Tablet | Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC0-inf) | 1109.2 h*ng/mL | Geometric Coefficient of Variation 72.9 |
Secondary
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.
Time frame: From the first dose of study drug administration until 30 days after the last dose of study drug administration, assessed up to 14 Months
Population: Safety analysis set included all subjects who received at least one dose of IMP.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A: Pimasertib 60 mg Capsule | Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation | Serious TEAEs | 1 subjects |
| Part A: Pimasertib 60 mg Capsule | Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation | TEAEs | 19 subjects |
| Part A: Pimasertib 60 mg Capsule | Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation | TEAEs leading to discontinuation | 0 subjects |
| Part A: Pimasertib 60 mg Tablet | Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation | Serious TEAEs | 0 subjects |
| Part A: Pimasertib 60 mg Tablet | Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation | TEAEs | 20 subjects |
| Part A: Pimasertib 60 mg Tablet | Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation | TEAEs leading to discontinuation | 0 subjects |
| Part B: Pimasertib Capsule | Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation | TEAEs | 38 subjects |
| Part B: Pimasertib Capsule | Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation | TEAEs leading to discontinuation | 13 subjects |
| Part B: Pimasertib Capsule | Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation | Serious TEAEs | 19 subjects |
Secondary
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).
Time frame: 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
Population: Safety analysis set included all subjects who received at least one dose of IMP.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Pimasertib 60 mg Capsule | Part B: Number of Subjects Who Experienced Complete Response (CR) | 0 subjects |
Secondary
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.
Time frame: 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
Population: Safety analysis set included all subjects who received at least one dose of IMP.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Pimasertib 60 mg Capsule | Part B: Number of Subjects Who Experienced Partial Response (PR) | 1 subjects |
Secondary
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.
Time frame: 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
Population: Safety analysis set included all subjects who received at least one dose of IMP.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Pimasertib 60 mg Capsule | Part B: Number of Subjects Who Experienced Progressive Disease (PD) | 15 subjects |
Secondary
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.
Time frame: 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
Population: Safety analysis set included all subjects who received at least one dose of IMP.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Pimasertib 60 mg Capsule | Part B: Number of Subjects Who Experienced Stable Disease (SD) | 10 subjects |
Secondary
Terminal Rate Constant (λz)
Time frame: 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
Population: PK analysis set included all subjects who received the Part A IMP, had compliance with IMP intake in Part A, at least one post-treatment PK sample from each treatment period and absence of protocol deviations affecting bioavailability. Here N (number of participants analyzed) signifies the number of subjects analysed for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Pimasertib 60 mg Capsule | Terminal Rate Constant (λz) | 0.16 1/h |
| Part A: Pimasertib 60 mg Tablet | Terminal Rate Constant (λz) | 0.15 1/h |
Secondary
Time to Reach Maximum Observed Plasma Concentration (Tmax)
Time frame: 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
Population: PK analysis set included all subjects who received the Part A IMP, had compliance with IMP intake in Part A, at least one post-treatment PK sample from each treatment period and absence of protocol deviations affecting bioavailability.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Pimasertib 60 mg Capsule | Time to Reach Maximum Observed Plasma Concentration (Tmax) | 0.750 hour |
| Part A: Pimasertib 60 mg Tablet | Time to Reach Maximum Observed Plasma Concentration (Tmax) | 0.517 hour |