Neoplasms
Conditions
Brief summary
P-cadherin may play a part in tumor growth; PF-03732010 is a new drug that inhibits P-cadherin. This study will test how well the drug is tolerated, and what effects there might be. Blood will also be taken to measure the amount of drug in blood.
Interventions
DRUGPF-03732010
IV infusion. Escalating dose levels, starting at 0.5 mg/kg to Maximum Tolerated Dose. Cycle length of 4 weeks for first cycle, and 2 weekly for subsequently cycles was originally explored, yet based on emerging PK data the Cycle 1 duration is 2 weeks and then weekly. Number of Cycles: Until Progression or unacceptable toxicity develops.
Sponsors
Pfizer
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Advanced solid tumors refractory to (or intolerant of) established therapy known to provide clinical benefit, or for which there is no standard therapy * Age \>= 18 years of age * Adequate bone marrow function as defined by: absolute neutrophil count (ANC) ≥1500/uL, hemoglobin ≥ 9 g/dL, platelets \> 100,000/uL * Adequate liver function as defined by: bilirubin \< 1.5 x ULN, AST, ALT and ALP \< 2.5 x ULN, or \< 5 x ULN with documented liver and/or bone metastases * Serum creatinine \< 1.5 x ULN * ECOG status 0-1 * Availability of biopsy tumor tissue (or fine needle aspirate) for testing of P-cadherin expression * Tumor tissue (or fine needle aspirate) showing over-expression of P-cadherin * Must be able to give written informed consent * Be able to comply with scheduled study visits, treatment plans, laboratory tests and other procedures
Exclusion criteria
* Chemotherapy, radiotherapy, or any investigational cancer therapy within 4 weeks of study entry * Patients with carcinomatous meningitis or untreated brain metastases. * History of significant low platelet count, and/or bleeding disorders, requiring medical or surgical intervention * History of significant bleeding episodes within 6 months, unless the source of bleeding has been resected
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Maximum Tolerated Dose (MTD) | Baseline up to end of treatment (EOT) or withdrawal assessed up to Day 7 of last cycle |
| Recommended Phase-2 Dose (RP2D) | Baseline up to EOT or withdrawal assessed up to Day 7 of last cycle |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Minimum Observed Serum Trough Concentration (Cmin) | 0 (pre-dose), 0.5, 1, 1.5, 2, 5, 10, 24 hrs after the start of infusion of first dose, Day 3, 5, 8, 11 of cycle 1; pre-dose and 1 hr after start of infusion in every other cycle starting from cycle 2 up to Week 4, 8 and 12 after last dose or withdrawal | — |
| Time to Reach Maximum Observed Serum Concentration (Tmax) | 0 (pre-dose), 0.5, 1, 1.5, 2, 5, 10, 24 hrs after the start of infusion of first dose, Day 3, 5, 8, 11 of cycle 1; pre-dose and 1 hr after start of infusion in every other cycle starting from cycle 2 up to Week 4, 8 and 12 after last dose or withdrawal | — |
| Maximum Observed Serum Concentration (Cmax) | 0 (pre-dose), 0.5, 1, 1.5, 2, 5, 10, 24 hrs after the start of infusion of first dose, Day 3, 5, 8, 11 of cycle 1; pre-dose and 1 hr after start of infusion in every other cycle starting from cycle 2 up to Week 4, 8 and 12 after last dose or withdrawal | — |
| Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-14 Day)] | 0 (pre-dose), 0.5, 1, 1.5, 2, 5, 10, 24 hrs after the start of infusion of first dose, Day 3, 5, 8, 11 of cycle 1; pre-dose and 1 hr after start of infusion in every other cycle starting from cycle 2 up to Week 4, 8 and 12 after last dose or withdrawal | AUC (0-14)= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-14 day). |
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | 0 (pre-dose), 0.5, 1, 1.5, 2, 5, 10, 24 hrs after the start of infusion of first dose, Day 3, 5, 8, 11 of cycle 1; pre-dose and 1 hr after start of infusion in every other cycle starting from cycle 2 up to Week 4, 8 and 12 after last dose or withdrawal | Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). |
| Clearance (CL) | 0 (pre-dose), 0.5, 1, 1.5, 2, 5, 10, 24 hrs after the start of infusion of first dose, Day 3, 5, 8, 11 of cycle 1; pre-dose and 1 hr after start of infusion in every other cycle starting from cycle 2 up to Week 4, 8 and 12 after last dose or withdrawal | Clearance of a drug is 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 (Vd) | 0 (pre-dose), 0.5, 1, 1.5, 2, 5, 10, 24 hrs after the start of infusion of first dose, Day 3, 5, 8, 11 of cycle 1; pre-dose and 1 hr after start of infusion in every other cycle starting from cycle 2 up to Week 4, 8 and 12 after last dose or withdrawal | 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 blood concentration of a drug. |
| Number of Participants With Objective Response of Complete Response or Partial Response | Baseline to disease progression or 4 weeks after the first dose and then every 6 weeks up to Week 37 | Number of participants with objective response based assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST). CR are those that persist on repeat imaging study at least 4 weeks after initial documentation of response. PR are those with at least 30 percent decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions. |
| Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-28 Day)] | 0 (pre-dose), 0.5, 1, 1.5, 2, 5, 10, 24 hrs after the start of infusion of first dose, Day 3, 5, 8, 11 of cycle 1; pre-dose and 1 hr after start of infusion in every other cycle starting from cycle 2 up to Week 4, 8 and 12 after last dose or withdrawal | AUC (0-28 day)= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-28 day). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Circulating Tumor Cells (CTC) Concentration in Blood | Pre-dose (baseline), Day 8 cycle 1, Day 1 Cycle 2 and Day 1 of every other cycle starting from cycle 3 up to EOT or withdrawal | — |
| Change From Baseline in Leucocyte Subtypes | Baseline, Day 1 cycle 1, Day 1 Cycle 2, Day 1 of every other cycle starting from cycle 3 up to EOT or withdrawal | — |
| Change From Baseline in Cytokine Concentration | Pre-dose (baseline), 1, 6 and 24 hrs after start of infusion on Day 1 cycle 1 | — |
| Change From Baseline in Tumor Proteins Related to P-cadherin Signaling and/or Tumor Proliferation or Apoptosis by Immunohistochemistry (IHC) | Baseline and cycle 3 | — |
| Time to Disease Progression | Baseline to disease progression or 4 weeks after the first dose and then every 6 weeks up to Week 37 | Time in weeks from start of study treatment to first documentation of objective disease progression or death due to disease, whichever comes first. |
| Human Anti-Human Antibody (HAHA) Levels | Pre-dose on Day 1 of Cycle 2 and Day 1 of every other cycle up to Week 4, 8 and 12 after the last dose or withdrawal | HAHA are indicators of immunogenicity to PF-03732010. |
| Change From Baseline in Standardized Uptake Values (SUV) of 18F-fluoro-3'-Deoxy-3'-L-fluorothymidine Positron Emission Tomography (FLT-PET) | Baseline, cycle 3 and after 8 weeks | — |
Countries
Australia, South Korea, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| PF-03732010 0.5 mg/kg Biweekly PF-03732010 infusion 0.5 mg/kg IV administered over 1 hr on Day 1 of cycle 1 (28 days cycle) and subsequently on Day 1 of each cycle (dosing interval of 14 days). | 3 |
| PF-03732010 1.0 mg/kg Biweekly PF-03732010 infusion 1.0 mg/kg IV administered over 1 hr on Day 1 of cycle 1 (28 days cycle) and subsequently on Day 1 of each cycle (dosing interval of 14 days). | 3 |
| PF-3732010 2.0 mg/kg Biweekly PF-03732010 infusion 2.0 mg/kg IV administered over 1 hr on Day 1 of cycle 1 (28 days cycle) and subsequently on Day 1 of each cycle (dosing interval of 14 days). | 4 |
| PF-03732010 4.0 mg/kg Biweekly PF-03732010 infusion 4.0 mg/kg IV administered over 1 hr on Day 1 of cycle 1 (28 days cycle) and subsequently on Day 1 of each cycle (dosing interval of 14 days). | 3 |
| PF-03732010 8.0 mg/kg Biweekly PF-03732010 infusion 8.0 mg/kg IV administered over 1 hr on Day 1 of cycle 1 (28 days cycle) and subsequently on Day 1 of each cycle (dosing interval of 14 days). | 2 |
| PF-03732010 15.0 mg/kg Biweekly PF-03732010 infusion 15.0 mg/kg IV administered over 1 hr on Day 1 of cycle 1 (28 days cycle) and subsequently on Day 1 of each cycle (dosing interval of 14 days). | 3 |
| PF-03732010 4.0 mg/kg Weekly PF-03732010 infusion 4.0 mg/kg IV administered over 1 hr on Day 1 of cycle 1 (14 days cycle) and subsequently on Day 1 of each cycle (dosing interval of 7 days). | 3 |
| PF-03732010 8.0 mg/kg Weekly PF-03732010 infusion 8.0 mg/kg IV administered over 1 hr on Day 1 of cycle 1 (14 days cycle) and subsequently on Day 1 of each cycle (dosing interval of 7 days). | 5 |
| PF-03732010 15.0 mg/kg Weekly PF-03732010 infusion 15.0 mg/kg IV administered over 1 hr on Day 1 of cycle 1 (14 days cycle) and subsequently on Day 1 of each cycle (dosing interval of 7 days). | 17 |
| Total | 43 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Death | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Global deterioration of health | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Objective progression or relapse | 2 | 3 | 3 | 2 | 2 | 3 | 2 | 5 | 15 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | PF-03732010 0.5 mg/kg Biweekly | PF-03732010 1.0 mg/kg Biweekly | PF-3732010 2.0 mg/kg Biweekly | PF-03732010 4.0 mg/kg Biweekly | PF-03732010 8.0 mg/kg Biweekly | PF-03732010 15.0 mg/kg Biweekly | PF-03732010 4.0 mg/kg Weekly | PF-03732010 8.0 mg/kg Weekly | PF-03732010 15.0 mg/kg Weekly | Total |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Customized 18 to 44 years | 0 participants | 1 participants | 0 participants | 1 participants | 0 participants | 1 participants | 0 participants | 1 participants | 1 participants | 5 participants |
| Age, Customized 45 to 64 years | 1 participants | 1 participants | 3 participants | 2 participants | 2 participants | 1 participants | 1 participants | 3 participants | 13 participants | 27 participants |
| Age, Customized Equal to or greater than 65 years | 2 participants | 1 participants | 1 participants | 0 participants | 0 participants | 1 participants | 2 participants | 1 participants | 3 participants | 11 participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 2 Participants | 7 Participants | 17 Participants |
| Sex: Female, Male Male | 2 Participants | 1 Participants | 3 Participants | 2 Participants | 1 Participants | 2 Participants | 2 Participants | 3 Participants | 10 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 4 / 4 | 3 / 3 | 2 / 2 | 3 / 3 | 3 / 3 | 5 / 5 | 13 / 17 |
| serious Total, serious adverse events | 1 / 3 | 0 / 3 | 2 / 4 | 0 / 3 | 0 / 2 | 1 / 3 | 1 / 3 | 0 / 5 | 4 / 17 |
Outcome results
Primary
Maximum Tolerated Dose (MTD)
Time frame: Baseline up to end of treatment (EOT) or withdrawal assessed up to Day 7 of last cycle
Population: MTD analysis population included all participants enrolled in the dose escalation part of the study who received at least 1 dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PF-03732010 0.5 mg/kg Biweekly | Maximum Tolerated Dose (MTD) | NA mg/kg |
| PF-03732010 1.0 mg/kg Biweekly | Maximum Tolerated Dose (MTD) | NA mg/kg |
| PF-3732010 2.0 mg/kg Biweekly | Maximum Tolerated Dose (MTD) | NA mg/kg |
| PF-03732010 4.0 mg/kg Biweekly | Maximum Tolerated Dose (MTD) | NA mg/kg |
| PF-03732010 8.0 mg/kg Biweekly | Maximum Tolerated Dose (MTD) | NA mg/kg |
| PF-03732010 15.0 mg/kg Biweekly | Maximum Tolerated Dose (MTD) | NA mg/kg |
| PF-03732010 4.0 mg/kg Weekly | Maximum Tolerated Dose (MTD) | NA mg/kg |
| PF-03732010 8.0 mg/kg Weekly | Maximum Tolerated Dose (MTD) | NA mg/kg |
| PF-03732010 15.0 mg/kg Weekly | Maximum Tolerated Dose (MTD) | NA mg/kg |
Primary
Recommended Phase-2 Dose (RP2D)
Time frame: Baseline up to EOT or withdrawal assessed up to Day 7 of last cycle
Population: Data was not analyzed, as development of the compound was terminated.
Secondary
Apparent Volume of Distribution (Vd)
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 blood concentration of a drug.
Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 5, 10, 24 hrs after the start of infusion of first dose, Day 3, 5, 8, 11 of cycle 1; pre-dose and 1 hr after start of infusion in every other cycle starting from cycle 2 up to Week 4, 8 and 12 after last dose or withdrawal
Population: Data was not summarized, as development of the compound was terminated.
Secondary
Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-14 Day)]
AUC (0-14)= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-14 day).
Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 5, 10, 24 hrs after the start of infusion of first dose, Day 3, 5, 8, 11 of cycle 1; pre-dose and 1 hr after start of infusion in every other cycle starting from cycle 2 up to Week 4, 8 and 12 after last dose or withdrawal
Population: Data was not summarized, as development of the compound was terminated.
Secondary
Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-28 Day)]
AUC (0-28 day)= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-28 day).
Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 5, 10, 24 hrs after the start of infusion of first dose, Day 3, 5, 8, 11 of cycle 1; pre-dose and 1 hr after start of infusion in every other cycle starting from cycle 2 up to Week 4, 8 and 12 after last dose or withdrawal
Population: Data was not summarized, as development of the compound was terminated.
Secondary
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast)
Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast).
Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 5, 10, 24 hrs after the start of infusion of first dose, Day 3, 5, 8, 11 of cycle 1; pre-dose and 1 hr after start of infusion in every other cycle starting from cycle 2 up to Week 4, 8 and 12 after last dose or withdrawal
Population: Data was not summarized, as development of the compound was terminated.
Secondary
Clearance (CL)
Clearance of a drug is 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: 0 (pre-dose), 0.5, 1, 1.5, 2, 5, 10, 24 hrs after the start of infusion of first dose, Day 3, 5, 8, 11 of cycle 1; pre-dose and 1 hr after start of infusion in every other cycle starting from cycle 2 up to Week 4, 8 and 12 after last dose or withdrawal
Population: Data was not summarized, as development of the compound was terminated.
Secondary
Maximum Observed Serum Concentration (Cmax)
Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 5, 10, 24 hrs after the start of infusion of first dose, Day 3, 5, 8, 11 of cycle 1; pre-dose and 1 hr after start of infusion in every other cycle starting from cycle 2 up to Week 4, 8 and 12 after last dose or withdrawal
Population: Data was not summarized, as development of the compound was terminated.
Secondary
Minimum Observed Serum Trough Concentration (Cmin)
Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 5, 10, 24 hrs after the start of infusion of first dose, Day 3, 5, 8, 11 of cycle 1; pre-dose and 1 hr after start of infusion in every other cycle starting from cycle 2 up to Week 4, 8 and 12 after last dose or withdrawal
Population: Data was not summarized, as development of the compound was terminated.
Secondary
Number of Participants With Objective Response of Complete Response or Partial Response
Number of participants with objective response based assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST). CR are those that persist on repeat imaging study at least 4 weeks after initial documentation of response. PR are those with at least 30 percent decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions.
Time frame: Baseline to disease progression or 4 weeks after the first dose and then every 6 weeks up to Week 37
Population: Data was not analyzed, as antitumor activity was not observed.
Secondary
Time to Reach Maximum Observed Serum Concentration (Tmax)
Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 5, 10, 24 hrs after the start of infusion of first dose, Day 3, 5, 8, 11 of cycle 1; pre-dose and 1 hr after start of infusion in every other cycle starting from cycle 2 up to Week 4, 8 and 12 after last dose or withdrawal
Population: Data was not summarized, as development of the compound was terminated.
Other Pre-specified
Change From Baseline in Circulating Tumor Cells (CTC) Concentration in Blood
Time frame: Pre-dose (baseline), Day 8 cycle 1, Day 1 Cycle 2 and Day 1 of every other cycle starting from cycle 3 up to EOT or withdrawal
Population: Data was not analyzed, as development of the compound was terminated.
Other Pre-specified
Change From Baseline in Cytokine Concentration
Time frame: Pre-dose (baseline), 1, 6 and 24 hrs after start of infusion on Day 1 cycle 1
Population: Data was not analyzed, as development of the compound was terminated.
Other Pre-specified
Change From Baseline in Leucocyte Subtypes
Time frame: Baseline, Day 1 cycle 1, Day 1 Cycle 2, Day 1 of every other cycle starting from cycle 3 up to EOT or withdrawal
Population: Data was not analyzed, as development of the compound was terminated.
Other Pre-specified
Change From Baseline in Standardized Uptake Values (SUV) of 18F-fluoro-3'-Deoxy-3'-L-fluorothymidine Positron Emission Tomography (FLT-PET)
Time frame: Baseline, cycle 3 and after 8 weeks
Population: Data was not analyzed, as development of the compound was terminated.
Other Pre-specified
Change From Baseline in Tumor Proteins Related to P-cadherin Signaling and/or Tumor Proliferation or Apoptosis by Immunohistochemistry (IHC)
Time frame: Baseline and cycle 3
Population: Data was not analyzed, as development of the compound was terminated.
Other Pre-specified
Human Anti-Human Antibody (HAHA) Levels
HAHA are indicators of immunogenicity to PF-03732010.
Time frame: Pre-dose on Day 1 of Cycle 2 and Day 1 of every other cycle up to Week 4, 8 and 12 after the last dose or withdrawal
Population: Data was not analyzed, as development of the compound was terminated.
Other Pre-specified
Time to Disease Progression
Time in weeks from start of study treatment to first documentation of objective disease progression or death due to disease, whichever comes first.
Time frame: Baseline to disease progression or 4 weeks after the first dose and then every 6 weeks up to Week 37
Population: Data was not analyzed, as antitumor activity was not observed.