A Study Of Oral Palbociclib (PD-0332991), A Cyclin-Dependent Kinase Inhibitor, In Patients With Advanced Cancer

NCT00141297 | Completed Phase 1 Results

• 1 other identifier: A5481001
• Study Type: interventional
• Target: 74
• Locations: 1 country
• Sites: 4

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.

Conditions

Neoplasms; Lymphoma, Non-Hodgkin

Keywords

Advanced cancer

Outcome Measures

Primary Outcomes (50)

• Number of Participants With Dose-Limiting Toxicities (DLT)

  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.

  Baseline up to 28 days

• Maximum Administered Dose (MAD)

  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.

  Baseline up to 28 days

• Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose Level (RP2D)

  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.

  Baseline up to 28 days

• Number of Dose-Limiting Toxicities (DLTs) Categorized as Per the Nature

  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.

  Baseline up to 28 days

• Number of Participants With Treatment Emergent Adverse Events Categorized by Severity

  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.

  Cycle 1, Cycle 2 up to 28 days after end of treatment (up to Cycle 93)

• Number of Participants With Treatment-Related Treatment Emergent Adverse Events

  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.

  Cycle 1, Cycle 2 up to 28 days after end of treatment (up to Cycle 93)

• Number of Participants Who Died Due to Adverse Event on the Basis of Relatedness to Study Drug

  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).

  Baseline up to 30 days after end of treatment (up to Cycle 93)

• 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 14/21 Dose-Corrected to 125 mg: Multiple Dose

  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.

  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)

• Maximum Observed Plasma Concentration (Cmax) on Day 1: Food Effect

  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.

  Hour 0 (pre-dose), 1, 2, 4, 7, 10 and 24 hours post-dose on C1D1, C2D1

• 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)

• 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)

• Time to Reach Maximum Observed Plasma Concentration (Tmax) on Day 14/21 Dose-Corrected to 125 mg: Multiple Dose

  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.

  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)

• Time to Reach Maximum Observed Plasma Concentration (Tmax) on Day 1: Food Effect

  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.

  Hour 0 (pre-dose), 1, 2, 4, 7, 10 and 24 hours post-dose on C1D1, C2D1

• Terminal Half-life (t½ ) on Day 1: Single Dose

  Terminal half-life is the time measured for the plasma concentration to decrease by one half.

  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

  Terminal half-life is the time measured for the plasma concentration to decrease by one half.

  Hour 0 (pre-dose), 1, 2, 4, 7, and 10 hours post-dose on Day 8 of Cycle 1 (C1D8)

• Terminal Half-life (t½) on Day 14/21 Dose-Corrected to 125 mg: Multiple Dose

  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.

  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 (t½ ) on Day 1: Food Effect

  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.

  Hour 0 (pre-dose), 1, 2, 4, 7, 10 and 24 hours post-dose on C1D1, C2D1

• Area Under the Curve From Time Zero to the Last Measured Concentration (AUClast) on Day 1: Single Dose

  Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast).

  Hour 0 (pre-dose), 1, 2, 4, 7, and 10 hours post-dose on Day 1 of Cycle 1 (C1D1)

• Area Under the Curve From Time Zero to the Last Measured Concentration (AUClast) on Day 8: Multiple Dose

  Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast).

  Hour 0 (pre-dose), 1, 2, 4, 7, and 10 hours post-dose on Day 8 of Cycle 1 (C1D8)

• Area Under the Curve From Time Zero to the Last Measured Concentration (AUClast) on Day 14/21 Dose-Corrected to 125 mg: Multiple Dose

  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.

  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 the Last Measured Concentration (AUClast) on Day 1: Food Effect

  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.

  Hour 0 (pre-dose), 1, 2, 4, 7, 10 and 24 hours post-dose on C1D1, C2D1

• 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

  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.

  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 Extrapolated Infinite Time [AUC (0 - ∞)] on Day 1: Single Dose

  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 - ∞).

  Hour 0 (pre-dose), 1, 2, 4, 7, and 10 hours post-dose on Day 1 of Cycle 1 (C1D1)

• Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] on Day 8: Multiple Dose

  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 - ∞).

  Hour 0 (pre-dose), 1, 2, 4, 7, and 10 hours post-dose on Day 8 of Cycle 1 (C1D8)

• Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] on Day 1: Food Effect

  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.

  Hour 0 (pre-dose), 1, 2, 4, 7, 10 and 24 hours post-dose on C1D1, C2D1

• Apparent Oral Clearance (CL/F) on Day 1: Single Dose

  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.

  Hour 0 (pre-dose), 1, 2, 4, 7, and 10 hours post-dose on Day 1 of Cycle 1 (C1D1)

• Apparent Oral Clearance (CL/F) on Day 8: Multiple Dose

  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.

  Hour 0 (pre-dose), 1, 2, 4, 7, and 10 hours post-dose on Day 8 of Cycle 1 (C1D8)

• Apparent Oral Clearance (CL/F) on Day 14/21 Dose-Corrected to 125 mg: Multiple Dose

  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.

  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)

• Apparent Oral Clearance (CL/F) on Day 1: Food Effect

  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.

  Hour 0 (pre-dose), 1, 2, 4, 7, 10 and 24 hours post-dose on C1D1, C2D1

• Apparent Volume of Distribution (Vz/F) on Day 1: Single Dose

  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.

  Hour 0 (pre-dose), 1, 2, 4, 7, and 10 hours post-dose on Day 1 of Cycle 1 (C1D1)

• Apparent Volume of Distribution (Vz/F) on Day 8: Multiple Dose

  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.

  Hour 0 (pre-dose), 1, 2, 4, 7, and 10 hours post-dose on Day 8 of Cycle 1 (C1D8)

• Apparent Volume of Distribution (Vz/F) on Day 14/21 Dose-Corrected to 125 mg: Multiple Dose

  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.

  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)

• Apparent Volume of Distribution (Vz/F) on Day 1: Food Effect

  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.

  Hour 0 (pre-dose), 1, 2, 4, 7, 10 and 24 hours post-dose on C1D1, C2D1

• Accumulation Ratio (Rac) on Day 8: Multiple Dose

  Rac at Day 8 = AUC (0-tau) at Day 8 divided by AUC (0-tau) at Day 1.

  Hour 0 (pre-dose), 1, 2, 4, 7, 10, and 24 hours post-dose on C1D1 and C1D8

• Accumulation Ratio (Rac) on Day 14/21 Dose-Corrected to 125 mg: Multiple Dose

  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.

  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 [Lambda (z)] on Day 1: Single Dose

  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.

  Hour 0 (pre-dose), 1, 2, 4, 7, and 10 hours post-dose on Day 1 of Cycle 1 (C1D1)

• Terminal Phase Rate Constant [Lambda (z)] on Day 8: Multiple Dose

  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.

  Hour 0 (pre-dose), 1, 2, 4, 7, and 10 hours post-dose on Day 8 of Cycle 1 (C1D8)

• Terminal Phase Rate Constant [Lambda (z)] on Day 14/21 Dose-Corrected to 125 mg: Multiple Dose

  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.

  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 [Lambda (z)] on Day 1: Food Effect

  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.

  Hour 0 (pre-dose), 1, 2, 4, 7, 10 and 24 hours post-dose on C1D1, C2D1

• Cumulative Amount of Drug Recovered Unchanged in the Urine (Ae): Single 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. Urine PK analysis was performed only in the MTD/RP2D groups (125 mg \[21/28 Days\] and 200 mg \[14/21 Days\]).

  Hour 0 (pre-dose) to 10 hours post-dose on C1D1

• Cumulative Amount of Drug Recovered Unchanged in the Urine (Ae): Food Effect

  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.

  Hour 0 (pre-dose) to 10 hours post-dose on C1D1

• Percent Dose Recovered Unchanged in Urine (Percent Ae): Single Dose

  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.

  Hour 0 (pre-dose) to 10 hours post-dose on C1D1

• Percent Dose Recovered Unchanged (Percent Ae) in Urine: Food Effect

  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.

  Hour 0 (pre-dose) to 10 hours post-dose on C1D1

• Number of Participants With Best Response

  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.

  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)

• Inhibition of Cyclin-dependent Kinases 4 and 6 (Cdk4/6) Based on Phosphorylated Retinoblastoma (p-Rb) in Tumor Tissue

  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.

  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)

• Correlation of Cyclin-dependent Kinases 4 and 6 (Cdk4/6) With PD 0322991 Dose

  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.

  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)

• Correlation of Cyclin-dependent Kinases 4 and 6 (Cdk4/6) With Exposure

  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.

  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)

• Correlation of Cyclin-dependent Kinases 4 and 6 (Cdk4/6) With Tumor Response

  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.

  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)

Study Arms (1)

PD-0332991

EXPERIMENTAL

Drug: PD-0332991

Interventions

PD-0332991 DRUG

Dose ranging study - evaluating two oral schedule: (1) 3/1 Schedule - PD-0332991 administered days 1-21 of a 28-day schedule, doses ranging from 25 to 150 mg once daily; (2) 2/1 Schedule - PD-0332991 administered days 1-14 of a 21-days schedule, doses ranging from 100 to 225 mg once daily

PD-0332991

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Pfizer: lead

Study Sites (4)

Karmanos Cancer Institute

Detroit, Michigan, 48201, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Abramson Cancer Center Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Pharmacy/PCAM/West Pavillion

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (2)

• Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer. 2009 Mar;9(3):153-66. doi: 10.1038/nrc2602.

  PMID: 19238148 DERIVED

• Vaughn DJ, Flaherty K, Lal P, Gallagher M, O'Dwyer P, Wilner K, Chen I, Schwartz G. Treatment of growing teratoma syndrome. N Engl J Med. 2009 Jan 22;360(4):423-4. doi: 10.1056/NEJMc0808558. No abstract available.

  PMID: 19164198 DERIVED

Related Links

• To obtain contact information for a study center near you, click here.

MeSH Terms

Conditions

Neoplasms; Lymphoma, Non-Hodgkin

Interventions

palbociclib

Condition Hierarchy (Ancestors)

Lymphoma; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Results Point of Contact

• Title: Pfizer ClinicalTrials.gov Call Center
• Organization: Pfizer, Inc.

ClinicalTrials.gov_Inquiries@pfizer.com

1-800-718-1021

Study Officials

• Pfizer CT.gov Call Center

  Pfizer

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 30, 2005
• First Posted: September 1, 2005
• Study Start: September 1, 2004
• Primary Completion: July 1, 2008
• Study Completion: December 1, 2014
• Last Updated: January 5, 2016
• Results First Posted: October 28, 2015

Record last verified: 2015-12

Locations

US (4)