Dose Finding Study Of CP-870,893, An Immune System Stimulating Antibody, In Combination With Paclitaxel And Carboplatin For Patients With Metastatic Solid Tumors

Study Overview
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Brief Summary
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This is a dose-finding study; therefore, there is no hypothesis testing

Official Title
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A Phase 1 Study Of CP- 870,893 In Combination With Paclitaxel And Carboplatin In Patients With Metastatic Solid Tumors

Conditions
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Neoplasms

Intervention / Treatment
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* Drug: Paclitaxel + Carboplatin + CP-870,893
* Drug: Paclitaxel + Carboplatin + CP-870,893


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with metastatic solid tumors, for whom carboplatin and paclitaxel are appropriate; Patients >18 years of age; Good performance status; Adequate bone marrow and organ function Exclusion Criteria: Previous treatment with any other compound that targets CD40 Current or planned concurrent treatment with any anticancer agent; Patients who have received bone marrow transplant; History of autoimmune disorder History (within the previous year) of heart failure or heart attack Cancer-associated coagulation disorders

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Schedule A<br>Schedule A (CP-870,893 administration schedule) | Drug: Paclitaxel + Carboplatin + CP-870,893<br>* Paclitaxel is administered intravenously on day 1 of a 21-day cycle at a dose of 175 mg/m^2. Carboplatin is administered intravenously on day 1 of a 21-day cycle at AUC 6. CP-870,893 is administered intravenously on DAY 3 of a 21-day cycle in escalating doses (0.1 mg/kg and 0.2 mg/kg)<br>|
| Other: Schedule B<br>Schedule B (CP-870,893 administration schedule) | Drug: Paclitaxel + Carboplatin + CP-870,893<br>* Paclitaxel is administered intravenously on day 1 of a 21-day cycle at a dose of 175 mg/m^2. Carboplatin is administered intravenously on day 1 of a 21-day cycle at AUC 6. CP-870,893 is administered intravenously on DAY 8 of a 21-day cycle in escalating doses (0.1 mg/kg and 0.2 mg/kg)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With First Cycle Dose Limiting Toxicities (DLTs) | Any of the following during first cycle of treatment and attributable to CP-870893: Grade (Gr) 4 neutropenia (absolute neutrophil count [ANC] <500 cells/mm^3) for ≥7 days; Gr 3 or 4 febrile neutropenia (ANC <1000/mm^3, fever ≥38.5 degrees Celsius; platelets ≤25,000 cells/mm^3); ≥Gr 3 non-hematological adverse event despite optimal supportive care; ≥Gr 3 cytokine release syndrome or acute infusion reaction; failure to recover to Gr <1 toxicity after delaying next cycle by maximum of 2 weeks; Day 3 or 8 ANC <1000 cells/mm^3 or platelets <80000 cells/mm^3, or non-hematologic toxicity ≥Gr 2. | Schedule (Sch) A Cycle 1 / Day 3 or Schedule B Cycle 1 / Day 8 up to Cycle 1 / Day 21 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Serum Concentration (Cmax) | Mean of individual observed Cmax values measured as micrograms per milliliter (mcg/mL). | Schedule A Day 3 of each 21 Day Cycle, Schedule B Day 8 of each 21 Day Cycle: Pre-dose, 5 minutes after end of infusion, and 2, 6, and 24 hours (hrs) post-dose up to a maximum of 8 cycles (6 months) | 
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | Area under the serum concentration time-curve from time zero to the last measured concentration. AUClast was estimated using non-compartmental methods on the sequence of sample measurements. Mean of individual observed AUClast values measured as nanograms multiplied by micrograms per milliliter (ng*mcg/mL). | Schedule A Day 3 of each 21 Day Cycle, Schedule B Day 8 of each 21 Day Cycle: Pre-dose, 5 minutes after end of infusion, and 2, 6, and 24 hours post-dose up to a maximum of 8 cycles (6 months) | 
| Tumor Response of Partial Response (PR) and Complete Response CR) According to Response Evaluation Criteria in Solid Tumors (RECIST) | Number of participants with objective response based assessment of confirmed complete response (CR) or confirmed partial response (PR) according to RECIST. Confirmed responses are those that persist on repeat imaging study at least 4 weeks after initial documentation of response. CR was defined as the disappearance of all target and nontarget lesions. PR was defined as a ≥30% decrease in the sum of the longest dimensions (LD) of the target lesions taking as a reference the baseline sum LD. | Schedule A and Schedule B: Baseline and Day 21 of every even numbered cycle up to a maximum of 8 cycles (6 months) | 
| Change in Cytokine Concentrations of Interleukin 6 (IL 6): Pre-dose Concentration (CYTO0), Maximum Post-dose Concentration (CYTOMAX) | Concentrations reported as the mean of the pre-dose values and the mean of the maximum post-dose values to show change. An increase in values indicates greater cytokine release from cells targeted by the antibody and may be associated with an infusion reaction. | Schedule A Cycle 1 / Day 3 and Schedule B Cycle 1 / Day 8: predose, end of infusion, 1 , 2, 4, 6, 24, and 48 hours postdose | 
| Change in Cytokine Concentrations of Tumor Necrosis Factor Alpha (TNF Alpha): CYTO0, CYTOMAX | Concentrations reported as the mean of the pre-dose values and the mean of the maximum post-dose values to show change. An increase in values indicates greater cytokine release from cells targeted by the antibody and may be associated with an infusion reaction. | Schedule A Cycle 1 / Day 3 and Schedule B Cycle 1 / Day 8: predose, end of infusion, 1 , 2, 4, 6, 24, and 48 hours postdose | 
| Change in Bone Marrow Derived Cells (B Cell) Surface Markers: CD19 Pre-dose Percentage (PD0), Maximum Post-dose Percentage (PDmax) | Assess activity of B cells (involved in production of antibodies) in presence of CP-870893. Clusters of differentiation (CD) are specific types of proteins on cell surface. CD19 is a B cell antigen receptor and is used to quantitate changes in proportion of B cells in peripheral blood as a consequence of therapy. Higher numbers may indicate a greater presence of CD19 on cell surface with increased potential for antigen response. Percentage of cells reported as the mean of the pre-dose values and the mean of the maximum post-dose values to show change. | Schedule A Cycle 1 / Day 3 and Schedule B Cycle 1 / Day 8: predose, 6, 24, and 48 hours postdose | 
| Change in Bone Marrow Derived Cells (B Cell) Surface Markers: CD40 PD0, PDmax | Assess activity of B cells in the presence of CP-870893. CD40 is a costimulatory protein and is a target for CP-870893. Measurement of CD40 on white blood cells provides a measure of target modulation by CP-870893. Higher numbers may indicate potential for increased activation of antigen presenting cells. Percentage of cells reported as the mean of the pre-dose values and the mean of the maximum post-dose values to show change. | Schedule A Cycle 1 / Day 3 and Schedule B Cycle 1 / Day 8: predose, 6, 24, and 48 hours postdose | 
| Change in Bone Marrow Derived Cells (B Cell) Surface Markers: CD23 PD0, PDmax | Assess activity of B cells in the presence of CP-870893. CD23 is a low-affinity receptor that has a role in transportation in antibody feedback regulation. Agents that engage CD40 have been reported to increase CD23 expression; increased CD23 expression may, therefore, serve as a marker for CD40 binding by CP-870893. Higher numbers may indicate a potential for increased antibody response. Percentage of cells reported as the mean of the pre-dose values and the mean of the maximum post-dose values to show change. | Schedule A Cycle 1 / Day 3 and Schedule B Cycle 1 / Day 8: predose, 6, 24, and 48 hours postdose | 
| Change in Bone Marrow Derived Cells (B Cell) Surface Markers: CD54 PD0, PDmax | Assess activity of B cells in presence of CP-870893. CD54 is an intercellular adhesion molecule. When activated, leukocytes bind to endothelial cells via CD54 and then transmigrate into tissues. Agents that engage CD40 have been reported to increase CD54 expression; increased CD54 expression may, therefore, serve as a marker for CD40 binding by CP-870893. Higher numbers may indicate potential for increased immune response. Percentage of cells reported as the mean of the pre-dose values and the mean of the maximum post-dose values to show change. | Schedule A Cycle 1 / Day 3 and Schedule B Cycle 1 / Day 8: predose, 6, 24, and 48 hours postdose | 
| Change in Bone Marrow Derived Cells (B Cell) Surface Markers: CD86 PD0, PDmax | Assess activity of B cells in presence of CP-870893. CD86 is a protein expressed on antigen-presenting cells and provides co-stimulatory signals for T cell (role in cell-modulated immunity) activation. Agents that engage CD40 have been reported to increase CD86 expression; increased CD86 expression may, therefore, serve as a marker for CD40 binding by CP-870893. Higher numbers may indicate potential for increased immune response. Percentage of cells reported as the mean of the pre-dose values and the mean of the maximum post-dose values to show change. | Schedule A Cycle 1 / Day 3 and Schedule B Cycle 1 / Day 8: predose, 6, 24, and 48 hours postdose | 
| Change in Bone Marrow Derived Cells (B Cell) Surface Markers: Human Leukocyte Antigen (HLA-DR) PD0, PDmax | Assess activity of B cells in presence of CP-870893. HLA-DR is a component of the Major Histocompatibility Complex in humans and presents antigens for recognition by the immune system. Agents that engage CD40 have been reported to increase HLA-DR expression; increased HLA-DR expression may serve as a marker for CD40 binding by CP-870893. Positive values may indicate greater presence of cells associated with potential for antibody production. Percentage of cells reported as the mean of the pre-dose values and the mean of the maximum post-dose values to show change. | Schedule A Cycle 1 / Day 3 and Schedule B Cycle 1 / Day 8: predose, 6, 24, and 48 hours postdose | 
| Total and Neutralizing Human Antihuman Antibody (HAHA) Titer | HAHA assessed as an indicator of immunogenicity to CP-870893. | Schedule A Day 3 of each 21 Day Cycle, Schedule B Day 8 of each 21 Day Cycle: Pre-dose up to a maximum of 8 cycles (6 months) |