Advanced Non-Hematologic Malignancies
Conditions
Keywords
Neoplasms, monoclonal antibody, PF-04605412, advanced metastatic solid tumors
Brief summary
Dose finding study of the MoaB PF-04605412 directed against the alpha5beta1 integrin. Main objective is to define the MTD (maximum tolerated dose) or MAD (maximum administrable dose) in cancer patients pre treated or unresponsive to standard therapies.
Interventions
DRUGPF-04605412
PF-04605412 will be administered as 2 hr IV infusion every 4 or 2 weeks. Start dose is 7.5 mg. Multiple doses are foreseen. Treatment will continue until intolerable toxicity, progression of disease or patient's refusal
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
* Histologically or cytologically confirmed advanced measurable or evaluable solid tumors unresponsive to currently available therapies, or for which there is no curative therapy * Eastern Cooperative Oncology Group (ECOG) performance status 0 and 1 * Life expectancy more than12 weeks * Adequate bone marrow, liver and renal function
Exclusion criteria
* Known brain metastasis * Chemotherapy, radiotherapy, or any investigational cancer therapy within 4 weeks of start of screening procedures * Major surgical procedure within 4 weeks of start of screening procedures * Active bleeding disorder, including gastrointestinal bleeding, as evidenced by hematemesis, significant hemoptysis or melena in the past 6 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose-limiting Toxicities (DLT) | Baseline up to 6 weeks PF-04605412 | DLT was defined as any of the following events occurring during the first 28 days of study medication and considered at least possibly-related to study medication: any grade 3 or 4 clinically-relevant non-hematologic toxicity,any \>= Grade 3 adverse event (AE) graded by National Cancer Institute \[NCI\] Common Terminology Criteria for Adverse Events \[CTCAE\], version 3.0 without a clear alternative explanation to study treatment relationship occurring during the first 6 weeks of treatment with PF-04605412. DLT was used to determine maximum tolerated dose (MTD) in this study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Serum Concentration (Cmax) | Predose, 1, 2, 2.5, 3, 6, 10, 24 hours after the start of infusion on Day 1; Days 3, 5, 8, 11, 15, 22 of Cycle 1 | — |
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | Predose, 1, 2, 2.5, 3, 6, 10, 24 hours after the start of infusion on Day 1; Days 3, 5, 8, 11, 15, 22 of Cycle 1 | Area under the serum concentration time-curve from zero to the last measured concentration (AUClast). |
| Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - Inf)] | Predose, 1, 2, 2.5, 3, 6, 10, 24 hours after the start of infusion on Day 1; Days 3, 5, 8, 11, 15, 22 of Cycle 1 | AUC (0 - inf)= Area under the serum concentration versus time curve (AUC) from time zero (predose) to extrapolated infinite time (0 - inf). It is obtained from AUC (0 - t) plus AUC (t - inf). |
| Serum Decay Half-Life (t1/2) | Predose, 1, 2, 2.5, 3, 6, 10, 24 hours after the start of infusion on Day 1; Days 3, 5, 8, 11, 15, 22 of Cycle 1 | Serum decay half-life is the time measured for the plasma concentration to decrease by one half. |
| Time to Reach Maximum Observed Serum Concentration (Tmax) | Predose, 1, 2, 2.5, 3, 6, 10, 24 hours after the start of infusion on Day 1; Days 3, 5, 8, 11, 15, 22 of Cycle 1 | — |
| Systemic Clearance (CL) | Predose, 1, 2, 2.5, 3, 6, 10, 24 hours after the start of infusion on Day 1; Days 3, 5, 8, 11, 15, 22 of Cycle 1 | CL is a quantitative measure of the rate at which a drug substance is removed from the body. |
| Volume of Distribution at Steady State (Vss) | Predose, 1, 2, 2.5, 3, 6, 10, 24 hours after the start of infusion on Day 1; Days 3, 5, 8, 11, 15, 22 of Cycle 1 | 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. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state. |
| Number of Participants Positive for Anti-PF04605412 Antibodies | Baseline up to end of treatment | Serum samples were analyzed for anti-drug antibodies (ADA) or human anti-human antibodies (HAHA). This was used to evaluate immunogenicity. |
| Objective Response - Number of Participants With Objective Response | Baseline up to 6 weeks after the first infusion of PF-04605412 (end of Cycle 2) and approximately every 6 weeks thereafter only in the absence of progressive disease | Number of participants with objective response based on assessment of confirmed complete response (CR) or confirmed partial response (PR) according to RECIST. Confirmed responses are those that persist on repeat imaging study ≥4 weeks after initial documentation of response. Per RECIST v1.0: CR defined as disappearance of all target lesions and non-target lesions. PR defined as ≥30% decrease in sum of the longest diameters dimensions (LD) of the target lesions taking as a reference the baseline sum LD according to RECIST associated to non-progressive disease response for non target lesions. |
| Percent Change in Transfer Constant (Ktrans) From Baseline to Cycle 1 Day 15 | Screening, and Cycle 1 Day 15 | Percent change in Ktrans for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) from baseline to Cycle 1 day 15 aimed at defining the effect of PF-04605412 on tumor vasculature. |
| Number of Participants With CD68 Expression | Predose and postdose | Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies CD68. |
| Number of Participants With Tissue Macrophage Infiltration | Predose and postdose | Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against tissue macrophages. |
| Number of Participants With Integrin Alpha 5 Beta 1 Expression | Predose and postdose | Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against integrin alpha 5 beta 1. |
| Number of Participants With Granzyme B Expression | Predose and postdose | Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against Granzyme B. |
| Number of Participants With CD56 Expression | Predose and postdose | Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against CD56. |
| Number of Participants With CD16 Expression | Predose and postdose | Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against CD16. |
| Number of Participants With pFAK Expression | Predose and postdose | Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against pFAK. |
| Number of Participants With CD31 Expression | Predose and postdose | Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against CD31. |
| Number of Participants With Caspase 3 Expression | Predose and postdose | Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against Caspase 3. |
| Number of Participants With Ki67 Expression | Predose and postdose | Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against Ki67. |
| Number of Participants With Perforin Expression | Predose and postdose | Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against Perforin. |
| Percent Change in Initial Area Under the Curve (IAUC) | Screening, and Cycle 1 Day 15 | Percent change in the IAUC for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) from baseline to Cycle 1 Day 15. IAUC reflects the contrast distribution volume (extravascular extracellular space) in addition to contrast delivery and transport across the vascular endothelium. An IAUC value of zero indicates the absence of disease (ie, no leakage of the contrast agent into the synovial volume); therefore, an increase in this parameter indicates worsening disease (ie, greater permeability of the synovial membrane). |
Countries
United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| PF-04605412 7.5 mg PF-04605412 7.5 mg was administered intravenously as 2 hour infusion. The first cycle lasted 4 weeks and the following cycles lasted 2 weeks each. Treatment was continued until intolerable toxicity, disease progression or participant withdrawal. | 8 |
| PF-04605412 11.25 mg PF-04605412 11.25 mg was administered intravenously as 2 hour infusion. The first cycle lasted 4 weeks and the following cycles lasted 2 weeks each. Treatment was continued until intolerable toxicity, disease progression or participant withdrawal. | 5 |
| PF-04605412 16.9 mg PF-04605412 16.9 mg was administered intravenously as 2 hour infusion. The first cycle lasted 4 weeks and the following cycles lasted 2 weeks each. Treatment was continued until intolerable toxicity, disease progression or participant withdrawal. | 3 |
| PF-04605412 34 mg PF-04605412 34 mg was administered intravenously as 2 hour infusion. The first cycle lasted 4 weeks and the following cycles lasted 2 weeks each. Treatment was continued until intolerable toxicity, disease progression or participant withdrawal. | 5 |
| PF-04605412 68 mg PF-04605412 68 mg was administered intravenously as 2 hour infusion. The first cycle lasted 4 weeks and the following cycles lasted 2 weeks each. Treatment was continued until intolerable toxicity, disease progression or participant withdrawal. | 3 |
| PF-04605412 136 mg PF-04605412 136 mg was administered intravenously as 2 hour infusion. The first cycle lasted 4 weeks and the following cycles lasted 2 weeks each. Treatment was continued until intolerable toxicity, disease progression or participant withdrawal. | 9 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Admission to hospice | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Adverse Event | 4 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Death | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Infusion related AEs | 0 | 0 | 0 | 0 | 0 | 2 |
| Overall Study | Lost to Follow-up | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Progressive disease/clinical progression | 0 | 0 | 0 | 3 | 1 | 2 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 0 | 1 | 4 |
Baseline characteristics
| Characteristic | PF-04605412 7.5 mg | PF-04605412 11.25 mg | PF-04605412 16.9 mg | PF-04605412 34 mg | PF-04605412 68 mg | PF-04605412 136 mg | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 54 Years STANDARD_DEVIATION 10.3 | 54.2 Years STANDARD_DEVIATION 12.2 | 61.3 Years STANDARD_DEVIATION 5.5 | 51.8 Years STANDARD_DEVIATION 7.2 | 60.7 Years STANDARD_DEVIATION 12.5 | 59.3 Years STANDARD_DEVIATION 13.6 | 56.4 Years STANDARD_DEVIATION 10.9 |
| Sex: Female, Male Female | 4 Participants | 1 Participants | 1 Participants | 3 Participants | 1 Participants | 5 Participants | 15 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 2 Participants | 2 Participants | 2 Participants | 4 Participants | 18 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 |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 8 / 8 | 5 / 5 | 3 / 3 | 4 / 5 | 3 / 3 | 9 / 9 |
| serious Total, serious adverse events | 5 / 8 | 2 / 5 | 1 / 3 | 1 / 5 | 0 / 3 | 5 / 9 |
Outcome results
Primary
Number of Participants With Dose-limiting Toxicities (DLT)
DLT was defined as any of the following events occurring during the first 28 days of study medication and considered at least possibly-related to study medication: any grade 3 or 4 clinically-relevant non-hematologic toxicity,any \>= Grade 3 adverse event (AE) graded by National Cancer Institute \[NCI\] Common Terminology Criteria for Adverse Events \[CTCAE\], version 3.0 without a clear alternative explanation to study treatment relationship occurring during the first 6 weeks of treatment with PF-04605412. DLT was used to determine maximum tolerated dose (MTD) in this study.
Time frame: Baseline up to 6 weeks PF-04605412
Population: All subjects enrolled in the dose escalation part of the study who received at least one dose of study medication that remained on study and/or provided safety follow-up for at least 6 weeks, unless discontinuing due to a DLT. Subjects discontinuing the study due to DLT are included
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PF-04605412 7.5 mg | Number of Participants With Dose-limiting Toxicities (DLT) | 1 participants |
| PF-04605412 11.25 mg | Number of Participants With Dose-limiting Toxicities (DLT) | 0 participants |
| PF-04605412 16.9 mg | Number of Participants With Dose-limiting Toxicities (DLT) | 0 participants |
| PF-04605412 34 mg | Number of Participants With Dose-limiting Toxicities (DLT) | 0 participants |
| PF-04605412 68 mg | Number of Participants With Dose-limiting Toxicities (DLT) | 0 participants |
| PF-04605412 136 mg | Number of Participants With Dose-limiting Toxicities (DLT) | 1 participants |
Secondary
Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - Inf)]
AUC (0 - inf)= Area under the serum concentration versus time curve (AUC) from time zero (predose) to extrapolated infinite time (0 - inf). It is obtained from AUC (0 - t) plus AUC (t - inf).
Time frame: Predose, 1, 2, 2.5, 3, 6, 10, 24 hours after the start of infusion on Day 1; Days 3, 5, 8, 11, 15, 22 of Cycle 1
Population: The analyzed population is all enrolled subjects treated who had received at least 1 dose of PF-04605412 and completed sampling for PK profiles for PF-04605412; N = number of subjects who had reportable AUC (0 - inf).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF-04605412 7.5 mg | Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - Inf)] | 2000 ng*hr/mL | — |
| PF-04605412 16.9 mg | Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - Inf)] | 27650 ng*hr/mL | — |
| PF-04605412 34 mg | Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - Inf)] | 160600 ng*hr/mL | Geometric Coefficient of Variation 69 |
| PF-04605412 68 mg | Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - Inf)] | 505200 ng*hr/mL | Geometric Coefficient of Variation 86 |
| PF-04605412 136 mg | Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - Inf)] | 2053000 ng*hr/mL | Geometric Coefficient of Variation 28 |
Secondary
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast)
Area under the serum concentration time-curve from zero to the last measured concentration (AUClast).
Time frame: Predose, 1, 2, 2.5, 3, 6, 10, 24 hours after the start of infusion on Day 1; Days 3, 5, 8, 11, 15, 22 of Cycle 1
Population: The analyzed population is all enrolled subjects treated who had received at least 1 dose of PF-04605412 and completed sampling for PK profiles for PF-04605412; N = number of subjects who had reportable AUClast.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF-04605412 7.5 mg | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | 4784 nanogram*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 171 |
| PF-04605412 11.25 mg | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | 14440 nanogram*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 170 |
| PF-04605412 16.9 mg | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | 12930 nanogram*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 103 |
| PF-04605412 34 mg | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | 149400 nanogram*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 71 |
| PF-04605412 68 mg | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | 490600 nanogram*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 85 |
| PF-04605412 136 mg | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | 2047000 nanogram*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 28 |
Secondary
Maximum Observed Serum Concentration (Cmax)
Time frame: Predose, 1, 2, 2.5, 3, 6, 10, 24 hours after the start of infusion on Day 1; Days 3, 5, 8, 11, 15, 22 of Cycle 1
Population: The analyzed population is all enrolled subjects treated who had received at least 1 dose of PF-04605412 and completed sampling for PK profiles for PF-04605412; N = number of subjects who had reportable Cmax.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF-04605412 7.5 mg | Maximum Observed Serum Concentration (Cmax) | 578.3 nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 37 |
| PF-04605412 11.25 mg | Maximum Observed Serum Concentration (Cmax) | 1229 nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 27 |
| PF-04605412 16.9 mg | Maximum Observed Serum Concentration (Cmax) | 1826 nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 90 |
| PF-04605412 34 mg | Maximum Observed Serum Concentration (Cmax) | 6682 nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 11 |
| PF-04605412 68 mg | Maximum Observed Serum Concentration (Cmax) | 13400 nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 18 |
| PF-04605412 136 mg | Maximum Observed Serum Concentration (Cmax) | 34110 nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 37 |
Secondary
Number of Participants Positive for Anti-PF04605412 Antibodies
Serum samples were analyzed for anti-drug antibodies (ADA) or human anti-human antibodies (HAHA). This was used to evaluate immunogenicity.
Time frame: Baseline up to end of treatment
Population: All subjects enrolled in this study who were treated with at least one dose of PF-04605412.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PF-04605412 7.5 mg | Number of Participants Positive for Anti-PF04605412 Antibodies | 1 participants |
| PF-04605412 11.25 mg | Number of Participants Positive for Anti-PF04605412 Antibodies | 0 participants |
| PF-04605412 16.9 mg | Number of Participants Positive for Anti-PF04605412 Antibodies | 0 participants |
| PF-04605412 34 mg | Number of Participants Positive for Anti-PF04605412 Antibodies | 0 participants |
| PF-04605412 68 mg | Number of Participants Positive for Anti-PF04605412 Antibodies | 0 participants |
| PF-04605412 136 mg | Number of Participants Positive for Anti-PF04605412 Antibodies | 2 participants |
Secondary
Number of Participants With Caspase 3 Expression
Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against Caspase 3.
Time frame: Predose and postdose
Population: The data was not statistically analyzed as planned due to early study termination.
Secondary
Number of Participants With CD16 Expression
Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against CD16.
Time frame: Predose and postdose
Population: The analyzed population is all enrolled subjects treated who had received at least 1 dose of PF-04605412 and completed sampling for PK profiles for PF-04605412; N = number of subjects who had reportable CD16 expression.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PF-04605412 7.5 mg | Number of Participants With CD16 Expression | 6 Participants |
| PF-04605412 11.25 mg | Number of Participants With CD16 Expression | 2 Participants |
| PF-04605412 16.9 mg | Number of Participants With CD16 Expression | 2 Participants |
| PF-04605412 34 mg | Number of Participants With CD16 Expression | 3 Participants |
| PF-04605412 68 mg | Number of Participants With CD16 Expression | 1 Participants |
| PF-04605412 136 mg | Number of Participants With CD16 Expression | 6 Participants |
Secondary
Number of Participants With CD31 Expression
Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against CD31.
Time frame: Predose and postdose
Population: The data was not statistically analyzed as planned due to early study termination.
Secondary
Number of Participants With CD56 Expression
Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against CD56.
Time frame: Predose and postdose
Population: The analyzed population is all enrolled subjects treated who had received at least 1 dose of PF-04605412 and completed sampling for PK profiles for PF-04605412; N = number of subjects who had reportable CD56 expression.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PF-04605412 7.5 mg | Number of Participants With CD56 Expression | 6 Participants |
| PF-04605412 11.25 mg | Number of Participants With CD56 Expression | 2 Participants |
| PF-04605412 16.9 mg | Number of Participants With CD56 Expression | 2 Participants |
| PF-04605412 34 mg | Number of Participants With CD56 Expression | 3 Participants |
| PF-04605412 68 mg | Number of Participants With CD56 Expression | 1 Participants |
| PF-04605412 136 mg | Number of Participants With CD56 Expression | 6 Participants |
Secondary
Number of Participants With CD68 Expression
Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies CD68.
Time frame: Predose and postdose
Population: The data was not statistically analyzed as planned due to early study termination.
Secondary
Number of Participants With Granzyme B Expression
Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against Granzyme B.
Time frame: Predose and postdose
Population: The data was not statistically analyzed as planned due to early study termination.
Secondary
Number of Participants With Integrin Alpha 5 Beta 1 Expression
Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against integrin alpha 5 beta 1.
Time frame: Predose and postdose
Population: The data was not statistically analyzed as planned due to early study termination.
Secondary
Number of Participants With Ki67 Expression
Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against Ki67.
Time frame: Predose and postdose
Population: The data was not statistically analyzed as planned due to early study termination.
Secondary
Number of Participants With Perforin Expression
Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against Perforin.
Time frame: Predose and postdose
Population: The data was not statistically analyzed as planned due to early study termination.
Secondary
Number of Participants With pFAK Expression
Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against pFAK.
Time frame: Predose and postdose
Population: The data was not statistically analyzed as planned due to early study termination.
Secondary
Number of Participants With Tissue Macrophage Infiltration
Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against tissue macrophages.
Time frame: Predose and postdose
Population: The data was not statistically analyzed as planned due to early study termination.
Secondary
Objective Response - Number of Participants With Objective Response
Number of participants with objective response based on assessment of confirmed complete response (CR) or confirmed partial response (PR) according to RECIST. Confirmed responses are those that persist on repeat imaging study ≥4 weeks after initial documentation of response. Per RECIST v1.0: CR defined as disappearance of all target lesions and non-target lesions. PR defined as ≥30% decrease in sum of the longest diameters dimensions (LD) of the target lesions taking as a reference the baseline sum LD according to RECIST associated to non-progressive disease response for non target lesions.
Time frame: Baseline up to 6 weeks after the first infusion of PF-04605412 (end of Cycle 2) and approximately every 6 weeks thereafter only in the absence of progressive disease
Population: All subjects enrolled in this study who were treated with at least one dose of PF-04605412.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PF-04605412 7.5 mg | Objective Response - Number of Participants With Objective Response | 0 participants |
| PF-04605412 11.25 mg | Objective Response - Number of Participants With Objective Response | 0 participants |
| PF-04605412 16.9 mg | Objective Response - Number of Participants With Objective Response | 0 participants |
| PF-04605412 34 mg | Objective Response - Number of Participants With Objective Response | 0 participants |
| PF-04605412 68 mg | Objective Response - Number of Participants With Objective Response | 0 participants |
| PF-04605412 136 mg | Objective Response - Number of Participants With Objective Response | 0 participants |
Secondary
Percent Change in Initial Area Under the Curve (IAUC)
Percent change in the IAUC for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) from baseline to Cycle 1 Day 15. IAUC reflects the contrast distribution volume (extravascular extracellular space) in addition to contrast delivery and transport across the vascular endothelium. An IAUC value of zero indicates the absence of disease (ie, no leakage of the contrast agent into the synovial volume); therefore, an increase in this parameter indicates worsening disease (ie, greater permeability of the synovial membrane).
Time frame: Screening, and Cycle 1 Day 15
Population: The data was not statistically analyzed as planned due to early study termination.
Secondary
Percent Change in Transfer Constant (Ktrans) From Baseline to Cycle 1 Day 15
Percent change in Ktrans for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) from baseline to Cycle 1 day 15 aimed at defining the effect of PF-04605412 on tumor vasculature.
Time frame: Screening, and Cycle 1 Day 15
Population: The data was not statistically analyzed as planned due to early study termination.
Secondary
Serum Decay Half-Life (t1/2)
Serum decay half-life is the time measured for the plasma concentration to decrease by one half.
Time frame: Predose, 1, 2, 2.5, 3, 6, 10, 24 hours after the start of infusion on Day 1; Days 3, 5, 8, 11, 15, 22 of Cycle 1
Population: The analyzed population is all enrolled subjects treated who had received at least 1 dose of PF-04605412 and completed sampling for PK profiles for PF-04605412; N = number of subjects who had reportable t1/2.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PF-04605412 7.5 mg | Serum Decay Half-Life (t1/2) | 2.70 hours | — |
| PF-04605412 16.9 mg | Serum Decay Half-Life (t1/2) | 7.27 hours | — |
| PF-04605412 34 mg | Serum Decay Half-Life (t1/2) | 13.5 hours | Standard Deviation 3.99 |
| PF-04605412 68 mg | Serum Decay Half-Life (t1/2) | 19.2 hours | Standard Deviation 8.6 |
| PF-04605412 136 mg | Serum Decay Half-Life (t1/2) | 36.9 hours | Standard Deviation 3.96 |
Secondary
Systemic Clearance (CL)
CL is a quantitative measure of the rate at which a drug substance is removed from the body.
Time frame: Predose, 1, 2, 2.5, 3, 6, 10, 24 hours after the start of infusion on Day 1; Days 3, 5, 8, 11, 15, 22 of Cycle 1
Population: The analyzed population is all enrolled subjects treated who had received at least 1 dose of PF-04605412 and completed sampling for PK profiles for PF-04605412; N = number of subjects who had reportable CL.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF-04605412 7.5 mg | Systemic Clearance (CL) | 3.79 Liter/hour (L/hr) | — |
| PF-04605412 16.9 mg | Systemic Clearance (CL) | 0.95 Liter/hour (L/hr) | — |
| PF-04605412 34 mg | Systemic Clearance (CL) | 0.212 Liter/hour (L/hr) | Geometric Coefficient of Variation 61 |
| PF-04605412 68 mg | Systemic Clearance (CL) | 0.135 Liter/hour (L/hr) | Geometric Coefficient of Variation 58 |
| PF-04605412 136 mg | Systemic Clearance (CL) | 0.066 Liter/hour (L/hr) | Geometric Coefficient of Variation 21 |
Secondary
Time to Reach Maximum Observed Serum Concentration (Tmax)
Time frame: Predose, 1, 2, 2.5, 3, 6, 10, 24 hours after the start of infusion on Day 1; Days 3, 5, 8, 11, 15, 22 of Cycle 1
Population: The analyzed population is all enrolled subjects treated who had received at least 1 dose of PF-04605412 and completed sampling for PK profiles for PF-04605412; N = number of subjects who had reportable Tmax.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PF-04605412 7.5 mg | Time to Reach Maximum Observed Serum Concentration (Tmax) | 2.00 hours |
| PF-04605412 11.25 mg | Time to Reach Maximum Observed Serum Concentration (Tmax) | 3.04 hours |
| PF-04605412 16.9 mg | Time to Reach Maximum Observed Serum Concentration (Tmax) | 2.43 hours |
| PF-04605412 34 mg | Time to Reach Maximum Observed Serum Concentration (Tmax) | 2.52 hours |
| PF-04605412 68 mg | Time to Reach Maximum Observed Serum Concentration (Tmax) | 2.00 hours |
| PF-04605412 136 mg | Time to Reach Maximum Observed Serum Concentration (Tmax) | 6.03 hours |
Secondary
Volume of Distribution at Steady State (Vss)
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. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state.
Time frame: Predose, 1, 2, 2.5, 3, 6, 10, 24 hours after the start of infusion on Day 1; Days 3, 5, 8, 11, 15, 22 of Cycle 1
Population: The analyzed population is all enrolled subjects treated who had received at least 1 dose of PF-04605412 and completed sampling for PK profiles for PF-04605412; N = number of subjects who had reportable Vss.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF-04605412 7.5 mg | Volume of Distribution at Steady State (Vss) | 13.65 Liter | — |
| PF-04605412 16.9 mg | Volume of Distribution at Steady State (Vss) | 10.87 Liter | — |
| PF-04605412 34 mg | Volume of Distribution at Steady State (Vss) | 6.61 Liter | Geometric Coefficient of Variation 66 |
| PF-04605412 68 mg | Volume of Distribution at Steady State (Vss) | 5.91 Liter | Geometric Coefficient of Variation 22 |
| PF-04605412 136 mg | Volume of Distribution at Steady State (Vss) | 3.73 Liter | Geometric Coefficient of Variation 22 |