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Antibodies, Monoclonal

Immunoglobulins

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

PF-04605412

Pfizer CT.gov Call Center

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.

A Safety Study Of A Monoclonal Antibody Against A5B1 Integrin In Solid Tumors

A Phase 1 Safety, Pharmacokinetic And Pharmacodynamic Study Of The Anti-A5B1 Integrin Monoclonal Antibody PF-04605412 Administered Intravenously To Adult Patients With Advanced Or Metastatic Solid Tumors

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.

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

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

CL is a quantitative measure of the rate at which a drug substance is removed from the body.

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.

Serum samples were analyzed for anti-drug antibodies (ADA) or human anti-human antibodies (HAHA). This was used to evaluate immunogenicity.

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 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.

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).

Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against tissue macrophages.

Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against integrin alpha 5 beta 1.

Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies CD68.

Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against Granzyme B.

Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against CD56.

Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against CD16.

Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against pFAK.

Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against CD31.

Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against Caspase 3.

Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against Ki67.

Immunohistochemical staining of tissue biopsies was performed with monoclonal antibodies directed against Perforin.

Pfizer

The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.

PF-04605412 7.5 mg was administered intravenously as 2 hour infusion on Day 1 of each cycle. 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.

PF-04605412 7.5 mg

PF-04605412 11.25 mg was administered intravenously as 2 hour infusion on Day 1 of each cycle. 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.

PF-04605412 11.25 mg

PF-04605412 16.9 mg was administered intravenously as 2 hour infusion on Day 1 of each cycle. 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.

PF-04605412 16.9 mg

PF-04605412 34 mg was administered intravenously as 2 hour infusion on Day 1 of each cycle. 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.

PF-04605412 34 mg

PF-04605412 68 mg was administered intravenously as 2 hour infusion on Day 1 of each cycle. 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.

PF-04605412 68 mg

PF-04605412 136 mg was administered intravenously as 2 hour infusion on Day 1 of each cycle. 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.

PF-04605412 136 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.

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.

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.

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.

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.

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.

Total

Age, Continuous

Sex: Female, Male

The analyzed population is the total number of enrolled subjects who started treatment.

This study was terminated prematurely because PK data did not enable sufficient confidence in producing desired clinical benefit. Potential re-occurrence of cytokine mediated infusion reaction at higher doses did not support further development.

Pfizer ClinicalTrials.gov Call Center

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

Number of Participants With Dose-limiting Toxicities (DLT)

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.

Maximum Observed Serum Concentration (Cmax)

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.

Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast)

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).

Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - Inf)]

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.

Serum Decay Half-Life (t1/2)

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.

Time to Reach Maximum Observed Serum Concentration (Tmax)

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.

Systemic Clearance (CL)

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.

Volume of Distribution at Steady State (Vss)

All subjects enrolled in this study who were treated with at least one dose of PF-04605412.

Number of Participants Positive for Anti-PF04605412 Antibodies

Objective Response - Number of Participants With Objective Response

The data was not statistically analyzed as planned due to early study termination.

Percent Change in Transfer Constant (Ktrans) From Baseline to Cycle 1 Day 15

Percent Change in Initial Area Under the Curve (IAUC)

Number of Participants With Tissue Macrophage Infiltration

Number of Participants With Integrin Alpha 5 Beta 1 Expression

Number of Participants With CD68 Expression

Number of Participants With Granzyme B Expression

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.

Number of Participants With CD56 Expression

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.

Spots Global Cancer Trial Database for A Safety Study Of A Monoclonal Antibody Against A5B1 Integrin In Solid Tumors

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