A Study Of Oral Palbociclib (PD-0332991), A Cyclin-Dependent Kinase Inhibitor, In Patients With Advanced Cancer
- Registration Number
- NCT00141297
- Lead Sponsor
- Pfizer
- Brief Summary
PD-0332991 may work in cancer by stopping cancer cells from multiplying. PD-0332991 is in a new class of drugs called cyclin-dependent kinase (CDK inhibitors). This research study is the first time that PD-0332991 will be given to people. PD-0332991 is taken by mouth daily.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 74
- Advanced solid tumors (excluding SCLC and retinoblastoma) or follicular of diffuse large cell non-Hodgkin's lymphoma, histologically or cytologically proven at diagnosis which is refractory to or intolerant of established therapy know to provide clinical benefit for their condition; tumors must express Rb
- Adequate blood cell counts, kidney function and liver function and and ECOG score of 0, 1, or 2.
- Patients may have to have tumor biopsy before and after treatment.
- Prior stem cell or bone marrow transplant
- Uncontrolled infection, unstable or sever intercurrent medical condition, or current drug or alcohol abuse
- Active or unstable cardiac disease or history of heart attack within 6 months
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description PD-0332991 PD-0332991 -
- Primary Outcome Measures
Name Time Method Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose Level (RP2D) Baseline up to 28 days MTD was defined as the highest dose level studied for which the incidence of first cycle DLT was \<33%. Once MTD was determined, it was defined as RP2D. DLT is defined in Outcome Measure 1.
Maximum Administered Dose (MAD) Baseline up to 28 days Three new evaluable participants were to be assessed at each new dose level. The minimum time that these participants were to be followed after starting treatment was 1 cycle (28 or 21 days) before a new dose level could be opened. If none of these 3 participants experienced a DLT, the next higher dose level was to be opened on that schedule. If 1 participant developed a DLT, 3 more evaluable participants were to be enrolled at that dose level; if none of these additional 3 participants developed a DLT, the next higher dose level was to be opened on that schedule. If \>=2 participants experienced a first cycle DLT at the same dose level and schedule, that dose level was to be defined as the MAD for that schedule. No additional participants were to be entered at the MAD for that dosing schedule. DLT is defined in Outcome Measure 1.
Terminal Half-life (t½ ) on Day 1: Single Dose Hour 0 (pre-dose), 1, 2, 4, 7, and 10 hours post-dose on Day 1 of Cycle 1 (C1D1) Terminal half-life is the time measured for the plasma concentration to decrease by one half.
Number of Dose-Limiting Toxicities (DLTs) Categorized as Per the Nature Baseline up to 28 days DLT is defined in Outcome Measure 1. Hematologic (Grade 4 \[life-threatening or disabling\]) and non-hematologic (Grade 3 \[severe\], 4 \[life-threatening and disabling\], 5 \[resulting in death\]) DLTs are reported separately. A single participant may experience more than one DLT. Both treatment-related and treatment-unrelated DLT events were reported for this outcome measure.
Maximum Observed Plasma Concentration (Cmax) on Day 14/21 Dose-Corrected to 125 mg: Multiple Dose Hour 0 (pre-dose), 1, 2, 4, 7, 10 and 24 hours post-dose on C1D21 for participants receiving 125 mg (21/28 Days) and Hour 0 (pre-dose), 1, 2, 4, 7, 10 and 24 hours post-dose on C1D14 for participants receiving 200 mg (14/21 Days) The mean Cmax for 200 mg dose group (dose corrected to 125 mg) on Cycle 1 Day 14 (C1D14) and 125 mg dose group on Cycle 1 Day 21 (C1D21) was calculated. Only participants from 125 mg and 200 mg dose groups were reported.
Apparent Volume of Distribution (Vz/F) on Day 8: Multiple Dose Hour 0 (pre-dose), 1, 2, 4, 7, and 10 hours post-dose on Day 8 of Cycle 1 (C1D8) Volume of distribution is 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.
Accumulation Ratio (Rac) on Day 8: Multiple Dose Hour 0 (pre-dose), 1, 2, 4, 7, 10, and 24 hours post-dose on C1D1 and C1D8 Rac at Day 8 = AUC (0-tau) at Day 8 divided by AUC (0-tau) at Day 1.
Terminal Phase Rate Constant [Lambda (z)] on Day 1: Single Dose Hour 0 (pre-dose), 1, 2, 4, 7, and 10 hours post-dose on Day 1 of Cycle 1 (C1D1) Terminal phase rate constant is the absolute value of the slope of a linear regression during the terminal phase of the natural--logarithm transformed concentration--time profile.
Number of Participants With Dose-Limiting Toxicities (DLT) Baseline up to 28 days DLT: an adverse event occurring after initiation of PD 0332991 that met any following criteria: 1) Grade 4 hematologic toxicity (platelets less than \[\<\] 25000 per microliter (mcL), absolute neutrophil count \[ANC\] \<500/mcL, hemoglobin \[Hb\] \<6.5 gram per deciliter \[g/dL\]; 2) ANC \<1000/mcL associated with documented infection or fever greater than or equal to (\>=) 38.5 degrees Celsius; 3) \>=Grade 3 non-hematologic treatment-related toxicity. In an asymptomatic participant, Grade 3 corrected QT (QTc) prolongation (\>500 millisecond) (only if persisted with repeat testing and after correction of reversible causes \[electrolyte abnormalities or hypoxia\]); and 4) Inability to receive next dose of PD 0332991 within 1 week (+/-1 day) of last dose due to lack of hematologic recovery (platelets \<50000/mcL, ANC \<1000/mcL, and Hb \<8.0 g/dL) or due to prolonged non-hematologic toxicities of \>=Grade 3 severity. Occurrence of a DLT necessitated immediate interruption of scheduled study treatment.
Maximum Observed Plasma Concentration (Cmax) on Day 1: Single Dose Hour 0 (pre-dose), 1, 2, 4, 7, and 10 hours post-dose on Day 1 of Cycle 1 (C1D1) Maximum Observed Plasma Concentration (Cmax) on Day 8: Multiple Dose Hour 0 (pre-dose), 1, 2, 4, 7, and 10 hours post-dose on Day 8 of Cycle 1 (C1D8) Maximum Observed Plasma Concentration (Cmax) on Day 1: Food Effect Hour 0 (pre-dose), 1, 2, 4, 7, 10 and 24 hours post-dose on C1D1, C2D1 To determine the impact of food (specifically a high-fat meal) on PD 0332991 PK, participants were tested under fed and fasted conditions in crossover fashion. Each participant served as their own control. In this crossover fashion first dose was administered under either fed (high-fat meal) or fasted (10-hour fast) condition on Day 1 of Cycle 1 and 2. The first 6 participants were tested under fed (on C1D1) followed by fasted (on C2D1) conditions, the next 6 participants were tested under fasted (on C1D1) followed by fed (on C2D1) conditions. Only participants in PD 0332991 200 mg (14/21 days) and 125 mg (21/28 days) groups participated in food effect crossover and results are reported as per fed and fasted conditions. The high-fat meal was composed of around 800 to 1000 calories total, with fat composing around 50% of the total caloric content.
Time to Reach Maximum Observed Plasma Concentration (Tmax) on Day 8: Multiple Dose Hour 0 (pre-dose), 1, 2, 4, 7, and 10 hours post-dose on Day 8 of Cycle 1 (C1D8) Number of Participants With Treatment Emergent Adverse Events Categorized by Severity Cycle 1, Cycle 2 up to 28 days after end of treatment (up to Cycle 93) An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. For clinical description of nature (severity) of AEs, AEs were grades as: Grade 1: mild AE; Grade 2: moderate AE; Grade 3: severe AE; Grade 4: life-threatening or disabling AE; and Grade 5: death related to AE. AEs during Cycle 1 and AEs post Cycle 1 are reported separately.
Number of Participants With Treatment-Related Treatment Emergent Adverse Events Cycle 1, Cycle 2 up to 28 days after end of treatment (up to Cycle 93) A treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. AEs during Cycle 1 and AEs post Cycle 1 are reported separately.
Time to Reach Maximum Observed Plasma Concentration (Tmax) on Day 14/21 Dose-Corrected to 125 mg: Multiple Dose Hour 0 (pre-dose), 1, 2, 4, 7, 10 and 24 hours post-dose on C1D21 for participants receiving 125 mg (21/28 Days) and Hour 0 (pre-dose), 1, 2, 4, 7, 10 and 24 hours post-dose on C1D14 for participants receiving 200 mg (14/21 Days) The median Tmax for 200 mg dose group (dose corrected to 125 mg) on Cycle 1 Day 14 (C1D14) and 125 mg dose group on Cycle 1 Day 21 (C1D21) was calculated. Only participants from 125 mg and 200 mg dose groups were reported.
Time to Reach Maximum Observed Plasma Concentration (Tmax) on Day 1: Food Effect Hour 0 (pre-dose), 1, 2, 4, 7, 10 and 24 hours post-dose on C1D1, C2D1 To determine impact of food (specifically high-fat meal) on PD 0332991 PK, participants were tested under fed and fasted conditions in crossover fashion. Each participant served as their own control. In crossover fashion first dose was administered under either fed (high-fat meal) or fasted (10-hour fast) condition on Day 1 of Cycle 1 and 2. First 6 participants were tested under fed (on C1D1) followed by fasted (on C2D1) conditions, next 6 participants were tested under fasted (on C1D1) followed by fed (on C2D1) conditions. Only participants in PD 0332991 200 mg (14/21 days) and 125 mg (21/28 days) groups participated in food effect crossover and results are reported as per fed and fasted conditions. High-fat meal was composed of around 800 to 1000 calories total, with fat composing around 50% of total caloric content.
Area Under the Curve From Time Zero to the Last Measured Concentration (AUClast) on Day 1: Single Dose Hour 0 (pre-dose), 1, 2, 4, 7, and 10 hours post-dose on Day 1 of Cycle 1 (C1D1) Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast).
Number of Participants Who Died Due to Adverse Event on the Basis of Relatedness to Study Drug Baseline up to 30 days after end of treatment (up to Cycle 93) An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. Treatment. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. Relatedness \[to study drug\] was assessed by the investigator (Yes/No).
Time to Reach Maximum Observed Plasma Concentration (Tmax) on Day 1: Single Dose Hour 0 (pre-dose), 1, 2, 4, 7, and 10 hours post-dose on Day 1 of Cycle 1 (C1D1) Terminal Half-life (t½ ) on Day 8: Multiple Dose Hour 0 (pre-dose), 1, 2, 4, 7, and 10 hours post-dose on Day 8 of Cycle 1 (C1D8) Terminal half-life is the time measured for the plasma concentration to decrease by one half.
Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] on Day 8: Multiple Dose Hour 0 (pre-dose), 1, 2, 4, 7, and 10 hours post-dose on Day 8 of Cycle 1 (C1D8) AUC (0 - ∞) = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞).
Terminal Half-life (t½) on Day 14/21 Dose-Corrected to 125 mg: Multiple Dose Hour 0 (pre-dose), 1, 2, 4, 7, 10 and 24 hours post-dose on C1D21 for participants receiving 125 mg (21/28 Days) and Hour 0 (pre-dose), 1, 2, 4, 7, 10 and 24 hours post-dose on C1D14 for participants receiving 200 mg (14/21 Days) Terminal half-life is the time measured for the plasma concentration to decrease by one half. The mean t1/2 for 200 mg dose group (dose corrected to 125 mg) on Cycle 1 Day 14 (C1D14) and 125 mg dose group on Cycle 1 Day 21 (C1D21) was calculated. Only participants from 125 mg and 200 mg dose groups were reported.
Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] on Day 1: Single Dose Hour 0 (pre-dose), 1, 2, 4, 7, and 10 hours post-dose on Day 1 of Cycle 1 (C1D1) AUC (0 - ∞) = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞).
Apparent Oral Clearance (CL/F) on Day 8: Multiple Dose Hour 0 (pre-dose), 1, 2, 4, 7, and 10 hours post-dose on Day 8 of Cycle 1 (C1D8) Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
Accumulation Ratio (Rac) on Day 14/21 Dose-Corrected to 125 mg: Multiple Dose Hour 0 (pre-dose), 1, 2, 4, 7, 10 and 24 hours post-dose on C1D21 for participants receiving 125 mg (21/28 Days) and Hour 0 (pre-dose), 1, 2, 4, 7, 10 and 24 hours post-dose on C1D14 for participants receiving 200 mg (14/21 Days) Rac at Day 14/21 = AUC (0-tau) at Day 14/21 divided by AUC (0-tau) at Day 1. The mean Rac for 200 mg dose group (dose corrected to 125 mg) on Cycle 1 Day 14 (C1D14) and 125 mg dose group on Cycle 1 Day 21 (C1D21) was calculated. Only participants from 125 mg and 200 mg dose groups were reported.
Terminal Half-life (t½ ) on Day 1: Food Effect Hour 0 (pre-dose), 1, 2, 4, 7, 10 and 24 hours post-dose on C1D1, C2D1 To determine impact of food (specifically high-fat meal) on PD 0332991 PK, participants were tested under fed and fasted conditions in crossover fashion. Each participant served as their own control. In crossover fashion first dose was administered under either fed (high-fat meal) or fasted (10-hour fast) condition on Day 1 of Cycle 1 and 2. First 6 participants were tested under fed (on C1D1) followed by fasted (on C2D1) conditions, next 6 participants were tested under fasted (on C1D1) followed by fed (on C2D1) conditions. Only participants in PD 0332991 200 mg (14/21 days) and 125 mg (21/28 days) groups participated in food effect crossover and results were to be reported as per fed and fasted conditions. High-fat meal was composed of around 800 to 1000 calories total, with fat composing around 50% of total caloric content.
Area Under the Curve From Time Zero to the Last Measured Concentration (AUClast) on Day 14/21 Dose-Corrected to 125 mg: Multiple Dose Hour 0 (pre-dose), 1, 2, 4, 7, 10 and 24 hours post-dose on C1D21 for participants receiving 125 mg (21/28 Days) and Hour 0 (pre-dose), 1, 2, 4, 7, 10 and 24 hours post-dose on C1D14 for participants receiving 200 mg (14/21 Days) Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). The mean AUClast for 200 mg dose group (dose corrected to 125 mg) on Cycle 1 Day 14 (C1D14) and 125 mg dose group on Cycle 1 Day 21 (C1D21) was calculated. Only participants from 125 mg and 200 mg dose groups were reported.
Area Under the Curve From Time Zero to the Last Measured Concentration (AUClast) on Day 1: Food Effect Hour 0 (pre-dose), 1, 2, 4, 7, 10 and 24 hours post-dose on C1D1, C2D1 Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). To determine impact of food (specifically high-fat meal) on PD 0332991 PK, participants were tested under fed and fasted conditions in crossover fashion. Each participant served as their own control. In crossover fashion first dose was administered under either fed (high-fat meal) or fasted (10-hour fast) condition on Day 1 of Cycle 1 and 2. First 6 participants were tested under fed (on C1D1) followed by fasted (on C2D1) conditions, next 6 participants were tested under fasted (on C1D1) followed by fed (on C2D1) conditions. Only participants in PD 0332991 200 mg (14/21 days) and 125 mg (21/28 days) groups participated in food effect crossover and results are reported as per fed and fasted conditions. High-fat meal was composed of around 800 to 1000 calories total, with fat composing around 50% of total caloric content.
Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] on Day 1: Food Effect Hour 0 (pre-dose), 1, 2, 4, 7, 10 and 24 hours post-dose on C1D1, C2D1 AUC (0 - ∞) = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). To determine impact of food (specifically high-fat meal) on PD 0332991 PK, participants were tested under fed and fasted conditions in crossover fashion. Each participant served as their own control. In crossover fashion first dose was administered under either fed (high-fat meal) or fasted (10-hour fast) condition on Day 1 of Cycle 1 and 2. First 6 participants were tested under fed (on C1D1) followed by fasted (on C2D1) conditions, next 6 participants were tested under fasted (on C1D1) followed by fed (on C2D1) conditions. Only participants in PD 0332991 200 mg (14/21 days) and 125 mg (21/28 days) groups participated in food effect crossover and results were to be reported as per fed and fasted conditions. High-fat meal was composed of around 800 to 1000 calories total, with fat composing around 50% of total caloric content.
Apparent Oral Clearance (CL/F) on Day 1: Single Dose Hour 0 (pre-dose), 1, 2, 4, 7, and 10 hours post-dose on Day 1 of Cycle 1 (C1D1) Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. 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) on Day 14/21 Dose-Corrected to 125 mg: Multiple Dose Hour 0 (pre-dose), 1, 2, 4, 7, 10 and 24 hours post-dose on C1D21 for participants receiving 125 mg (21/28 Days) and Hour 0 (pre-dose), 1, 2, 4, 7, 10 and 24 hours post-dose on C1D14 for participants receiving 200 mg (14/21 Days) Volume of distribution is 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. The mean Vz/F for 200 mg dose group (dose corrected to 125 mg) on Cycle 1 Day 14 (C1D14) and 125 mg dose group on Cycle 1 Day 21 (C1D21) was calculated. Only participants from 125 mg and 200 mg dose groups were reported.
Area Under the Curve From Time Zero to the Last Measured Concentration (AUClast) on Day 8: Multiple Dose Hour 0 (pre-dose), 1, 2, 4, 7, and 10 hours post-dose on Day 8 of Cycle 1 (C1D8) Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast).
Area Under the Curve From Time Zero to End of the Dosing Interval [AUC(0 to Tau)] on Day 14/21 Dose-Corrected to 125 mg: Multiple Dose Hour 0 (pre-dose), 1, 2, 4, 7, 10 and 24 hours post-dose on C1D21 for participants receiving 125 mg (21/28 Days) and Hour 0 (pre-dose), 1, 2, 4, 7, 10 and 24 hours post-dose on C1D14 for participants receiving 200 mg (14/21 Days) Area under the curve from time zero to end of the dosing interval (24 hours) \[AUC (0-tau)\]. The mean AUC (0-tau) for 200 mg dose group (dose corrected to 125 mg) on Cycle 1 Day 14 (C1D14) and 125 mg dose group on Cycle 1 Day 21 (C1D21) was calculated. Only participants from 125 mg and 200 mg dose groups were reported.
Apparent Oral Clearance (CL/F) on Day 14/21 Dose-Corrected to 125 mg: Multiple Dose Hour 0 (pre-dose), 1, 2, 4, 7, 10 and 24 hours post-dose on C1D21 for participants receiving 125 mg (21/28 Days) and Hour 0 (pre-dose), 1, 2, 4, 7, 10 and 24 hours post-dose on C1D14 for participants receiving 200 mg (14/21 Days) Clearance of a drug is a measure of rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. The mean CL/F for 200 mg dose group (dose corrected to 125 mg) on Cycle 1 Day 14 (C1D14) and 125 mg dose group on Cycle 1 Day 21 (C1D21) was calculated. Only participants from 125 mg and 200 mg dose groups were reported.
Apparent Oral Clearance (CL/F) on Day 1: Food Effect Hour 0 (pre-dose), 1, 2, 4, 7, 10 and 24 hours post-dose on C1D1, C2D1 Clearance of a drug is a measure of rate at which a drug is metabolized or eliminated by normal biological processes. To determine impact of food (specifically high-fat meal) on PD 0332991 PK, participants were tested under fed and fasted conditions in crossover fashion. Each participant served as their own control. In crossover fashion first dose was administered under either fed (high-fat meal) or fasted (10-hour fast) condition on Day 1 of Cycle 1 and 2. First 6 participants were tested under fed (on C1D1) followed by fasted (on C2D1) conditions, next 6 participants were tested under fasted (on C1D1) followed by fed (on C2D1) conditions. Only participants in PD 0332991 200 mg (14/21 days) and 125 mg (21/28 days) groups participated in food effect crossover and results were to be reported as per fed and fasted conditions. High-fat meal was composed of around 800 to 1000 calories total, with fat composing around 50% of total caloric content.
Apparent Volume of Distribution (Vz/F) on Day 1: Single Dose Hour 0 (pre-dose), 1, 2, 4, 7, and 10 hours post-dose on Day 1 of Cycle 1 (C1D1) Volume of distribution is 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.
Apparent Volume of Distribution (Vz/F) on Day 1: Food Effect Hour 0 (pre-dose), 1, 2, 4, 7, 10 and 24 hours post-dose on C1D1, C2D1 Volume of distribution: theoretical volume in which total amount of drug would need to be uniformly distributed to produce desired plasma concentration. To determine impact of food (specifically high-fat meal) on PD 0332991 PK, participants were tested under fed and fasted conditions in crossover fashion. Each participant served as their own control. In crossover fashion first dose was administered under either fed (high-fat meal) or fasted (10-hour fast) condition on Day 1 of Cycle 1 and 2. First 6 participants were tested under fed (on C1D1) followed by fasted (on C2D1) conditions, next 6 participants were tested under fasted (on C1D1) followed by fed (on C2D1) conditions. Only participants in PD 0332991 200 mg (14/21 days) and 125 mg (21/28 days) groups participated in food effect crossover and results were to be reported as per fed and fasted conditions. High-fat meal was composed of around 800 to 1000 calories total, with fat composing around 50% of total caloric content.
Terminal Phase Rate Constant [Lambda (z)] on Day 8: Multiple Dose Hour 0 (pre-dose), 1, 2, 4, 7, and 10 hours post-dose on Day 8 of Cycle 1 (C1D8) Terminal phase rate constant is the absolute value of the slope of a linear regression during the terminal phase of the natural-logarithm transformed concentration-time profile.
Terminal Phase Rate Constant [Lambda (z)] on Day 1: Food Effect Hour 0 (pre-dose), 1, 2, 4, 7, 10 and 24 hours post-dose on C1D1, C2D1 Terminal phase rate constant: absolute value of slope of a linear regression during terminal phase of natural-logarithm transformed concentration-time profile. To determine impact of food (specifically high-fat meal) on PD 0332991 PK, participants were tested under fed and fasted conditions in crossover fashion. Each participant served as their own control. In crossover fashion first dose was administered under either fed (high-fat meal) or fasted (10-hour fast) condition on Day 1 of Cycle 1 and 2. First 6 participants were tested under fed (on C1D1) followed by fasted (on C2D1) conditions, next 6 participants were tested under fasted (on C1D1) followed by fed (on C2D1) conditions. Only participants in PD 0332991 200 mg (14/21 days) and 125 mg (21/28 days) groups participated in food effect crossover and results were to be reported as per fed and fasted conditions. High-fat meal was composed of around 800 to 1000 calories total, with fat composing around 50% of total caloric content.
Cumulative Amount of Drug Recovered Unchanged in the Urine (Ae): Single Dose Hour 0 (pre-dose) to 10 hours post-dose on C1D1 Ae is the cumulative amount of drug recovered unchanged in urine over the 10 hour collection interval. Cumulative amount was calculated as sum of urine drug concentration in sample volume for each collection interval. Urine PK analysis was performed only in the MTD/RP2D groups (125 mg \[21/28 Days\] and 200 mg \[14/21 Days\]).
Percent Dose Recovered Unchanged in Urine (Percent Ae): Single Dose Hour 0 (pre-dose) to 10 hours post-dose on C1D1 Percent of dose recovered unchanged in urine over the 10 hour collection interval=100\*(Ae divided by dose). Ae is the cumulative amount of drug recovered unchanged in urine over the 10 hour collection interval. Cumulative amount was calculated as sum of urine drug concentration in sample volume for each collection interval.
Terminal Phase Rate Constant [Lambda (z)] on Day 14/21 Dose-Corrected to 125 mg: Multiple Dose Hour 0 (pre-dose), 1, 2, 4, 7, 10 and 24 hours post-dose on C1D21 for participants receiving 125 mg (21/28 Days) and Hour 0 (pre-dose), 1, 2, 4, 7, 10 and 24 hours post-dose on C1D14 for participants receiving 200 mg (14/21 Days) Terminal phase rate constant is the absolute value of the slope of a linear regression during the terminal phase of the natural-logarithm transformed concentration-time profile. The mean lambda (z) for 200 mg dose group (dose corrected to 125 mg) on Cycle 1 Day 14 (C1D14) and 125 mg dose group on Cycle 1 Day 21 (C1D21) was calculated. Only participants from 125 mg and 200 mg dose groups were reported.
Percent Dose Recovered Unchanged (Percent Ae) in Urine: Food Effect Hour 0 (pre-dose) to 10 hours post-dose on C1D1 The percent Ae is defined in Outcome Measure 44. To determine impact of food (specifically high-fat meal) on PD 0332991 PK, participants were tested under fed and fasted conditions in crossover fashion. Each participant served as their own control. In crossover fashion first dose was administered under either fed (high-fat meal) or fasted (10-hour fast) condition on Day 1 of Cycle 1 and 2. First 6 participants were tested under fed (on C1D1) followed by fasted (on C2D1) conditions, next 6 participants were tested under fasted (on C1D1) followed by fed (on C2D1) conditions. Only participants in PD 0332991 200 mg (14/21 days) and 125 mg (21/28 days) groups participated in food effect crossover and results were to be reported as per fed and fasted conditions. High-fat meal was composed of around 800 to 1000 calories total, with fat composing around 50% of total caloric content.
Number of Participants With Best Response Baseline up to end of treatment, assessed at C1D1, C1D8, C1D15, C1D22, thereafter Day 1, 8, 15, and 22 of every other cycle up to end of treatment (up to Cycle 93) Number of participants with best response. Complete response (CR): disappearance of all target and non-target lesions. Partial Response (PR): \>=30% decrease in sum of longest diameter (LD) of lesions taking as reference baseline sum LD and no unequivocal progression in non-target lesions. Progressive disease (PD): \>=20% increase in sum of LD of lesions taking as a reference smallest sum of the LD since treatment start, or the appearance of \>=1 new lesion or unequivocal progression of existing non-target lesions. Stable disease (SD): neither shrinkage for PR nor increase for PD taking as reference smallest sum of LD since treatment start. SD was assessed following the first 2 cycles of treatment (\>=2 cycles), 4 cycles of treatment (\>=4 cycles), and 10 cycles of treatment (\>=10 cycles). Participants may be reported in more than 1 category of SD. Confirmed responses are those that persist on repeat imaging study at least 4 weeks after initial documentation of response.
Correlation of Cyclin-dependent Kinases 4 and 6 (Cdk4/6) With PD 0322991 Dose Baseline, C1D1, C1D8, C1D15, C1D22, thereafter Day 1, 8, 15, and 22 of every other cycle up to end of treatment (up to Cycle 93) Phosphorylation of the retinoblastoma (Rb) protein by Cdk4/6 is typically required for human cancer cell proliferation. Tumor biopsies were to be performed, to demonstrate inhibition of Cdk4/6 based on reduction in phosphorylated Rb (p-Rb) in tumor tissue, in correlation with respect to PD 0322991 dose.
Cumulative Amount of Drug Recovered Unchanged in the Urine (Ae): Food Effect Hour 0 (pre-dose) to 10 hours post-dose on C1D1 The Ae is defined in Outcome Measure 42. To determine impact of food (specifically high-fat meal) on PD 0332991 PK, participants were tested under fed and fasted conditions in crossover fashion. Each participant served as their own control. In crossover fashion first dose was administered under either fed (high-fat meal) or fasted (10-hour fast) condition on Day 1 of Cycle 1 and 2. First 6 participants were tested under fed (on C1D1) followed by fasted (on C2D1) conditions, next 6 participants were tested under fasted (on C1D1) followed by fed (on C2D1) conditions. Only participants in PD 0332991 200 mg (14/21 days) and 125 mg (21/28 days) groups participated in food effect crossover and results were to be reported as per fed and fasted conditions. High-fat meal was composed of around 800 to 1000 calories total, with fat composing around 50% of total caloric content.
Inhibition of Cyclin-dependent Kinases 4 and 6 (Cdk4/6) Based on Phosphorylated Retinoblastoma (p-Rb) in Tumor Tissue Baseline, C1D1, C1D8, C1D15, C1D22, thereafter Day 1, 8, 15, and 22 of every other cycle up to end of treatment (up to Cycle 93) Phosphorylation of the retinoblastoma (Rb) protein by Cdk4/6 is typically required for human cancer cell proliferation. Tumor biopsies were to be performed, to demonstrate inhibition of Cdk4/6 based on reduction in phosphorylated Rb (p-Rb) in tumor tissue and p-Rb levels (fold decrease) were to be reported.
Correlation of Cyclin-dependent Kinases 4 and 6 (Cdk4/6) With Exposure Baseline, C1D1, C1D8, C1D15, C1D22, thereafter Day 1, 8, 15, and 22 of every other cycle up to end of treatment (up to Cycle 93) Phosphorylation of the retinoblastoma (Rb) protein by Cdk4/6 is typically required for human cancer cell proliferation. Tumor biopsies were to be performed, to demonstrate inhibition of Cdk4/6 based on reduction in phosphorylated Rb (p-Rb) in tumor tissue, in correlation with PD 0322991 exposure.
Correlation of Cyclin-dependent Kinases 4 and 6 (Cdk4/6) With Tumor Response Baseline, C1D1, C1D8, C1D15, C1D22, thereafter Day 1, 8, 15, and 22 of every other cycle up to end of treatment (up to Cycle 93) Phosphorylation of the retinoblastoma (Rb) protein by Cdk4/6 is typically required for human cancer cell proliferation. Tumor biopsies were to be performed, to demonstrate inhibition of Cdk4/6 based on reduction in phosphorylated Rb (p-Rb) in tumor tissue, in correlation with tumor response.
- Secondary Outcome Measures
Name Time Method
Trial Locations
- Locations (4)
Karmanos Cancer Institute
🇺🇸Detroit, Michigan, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Abramson Cancer Center Hospital of the University of Pennsylvania
🇺🇸Philadelphia, Pennsylvania, United States
Pharmacy/PCAM/West Pavillion
🇺🇸Philadelphia, Pennsylvania, United States