A Dose Finding Study Of A New Medication, PF-00337210 That Will Possibly Decrease Blood Supply To Tumors

Neoplasm Clinical Trial

Official title:

Phase I, Open-Label, Multi-Center, Accelerated Dose Escalation Study Of The Anti-Angiogenesis Agent PF-00337210 In Patients With Advanced Solid Tumors

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01105533
• Other study ID #: A8051001
• Status: Completed
• Phase: Phase 1
• First received: April 14, 2010
• Last updated: February 13, 2013
• Start date: May 2006
• Est. completion date: September 2011

Study information

• Verified date: February 2013
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

This study will test a new cancer medication to determine if this medication will block blood supply to a tumor and decrease growth of a tumor. This study will also define the safety profile and define the safest dose of this new medication for people who have cancer.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 46
• Est. completion date: September 2011
• Est. primary completion date: October 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histologically or cytologically confirmed advanced solid tumors un-responsive to currently available therapies or for which there is no standard therapy.

• At least 1 measurable disease site as defined by Response Evaluation Criterion in Solid Tumors [RECIST].

• Adequate bone marrow, liver function and renal function as defined by protocol.

• Blood pressure Requirements During dose escalation - no evidence of pre-existing hypertension and no antihypertensive medications at baseline.

During dose expansion - patient's whose hypertension is controlled by antihypertensive therapy.

Exclusion Criteria:

• Chemotherapy, radiotherapy or any investigational therapy within 4 weeks of study entry

• Current use or anticipated need for drugs that are known CYP34 inhibitors or inducers.

• Patients with carcinomatous meningitis or un-treated brain metastases.

• Any acute cardiovascular incident within the past 12 months.

• Patients with active gastrointestinal bleeding or significant gastrointestinal abnormalities as defined by protocol

• Patients with no evidence of the following for 5 years: malignancy or metastatic disease of skin cancer (except melanoma), in situ cervical cancer or breast cancer or T1C prostate cancer.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Neoplasm

Intervention

Drug:
• PF-00337210
0.67mg Capsule Once Daily (Accelerated Dose Escalation) Continuous
• PF-00337210
1mg Capsule Once Daily (Dose Escalation) Continuous
• PF-00337210
2mg Capsule Once Daily (Dose Escalation) Continuous
• PF-00337210
4mg Capsule Once Daily (Dose Escalation) Continuous
• PF-00337210
6mg Capsule Once Daily (Dose Escalation) Continuous
• PF-00337210
9mg Capsule Once Daily (Dose Escalation) Continuous
• PF-00337210
8mg Capsule Once Daily (Dose Escalation) Continuous
• PF-00337210
4mg Capsule Twice Daily (Dose Escalation) Continuous
• PF-00337210
6mg Capsule Twice Daily (Dose Escalation) Continuous
• PF-00337210
6mg Capsule Twice Daily (Dose Expansion) Continuous

Locations

Country	Name	City	State
United States	Pfizer Investigational Site	Detroit	Michigan
United States	Pfizer Investigational Site	Detroit	Michigan
United States	Pfizer Investigational Site	Madison	Wisconsin

Sponsors (2)

Lead Sponsor	Collaborator
Pfizer	University of Wisconsin, Madison

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Effect of Food on Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-24)]	AUC (0-24)= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-24).	Pre-dose,0.5,1,2,4,6,8,18,20,24 hrs post-dose on Day 29 (fasted state), Day 30 (fed state) for once daily groups, pre-dose,0.5,1,2,4,6,8 hrs post-dose on Day 29 Day 29 (fasted state), Day 30 (fed state) for twice daily groups	No
Primary	Number of Participants With Dose-limiting Toxicities (DLTs)	DLTs included events occurring in Cycle 1: blood pressure of 180/110 millimeters of mercury (mmHg) or higher for 3 readings over 3 hours regardless of use of anti-hypertensive drugs or greater than (>) 160/100 mmHg for 3 readings over 3 days on maximum anti-hypertensive drugs; afebrile Grade 4 neutropenia for greater than or equal to (>=) 7 days or >=Grade 3 neutropenia associated with fever (1 reading of oral temperature >38.5 degree Celsius [degree C] or 3 readings of oral temperature >38.0 degree C in 24-hour period); Grade 4 thrombocytopenia; hemoptysis of >1/2 teaspoon of bright red blood per day; proteinuria of >=2 grams/24 hours; inability to resume PF-00337210 dosing at current dose level within 14 days of stopping due to treatment-related toxicity; >=Grade 3 nonhematological toxicities (except alopecia and blood pressure/hypertension); Grade 3 nonhematological toxicities that could be controlled to Grade 2 or less with appropriate treatment were not considered dose limiting.	Baseline up to Day 28	Yes
Primary	Maximum Tolerated Dose (MTD)	MTD: dose level at which no more than 1 of 6 participants experienced DLT during Cycle 1. DLTs: blood pressure of 180/110 mmHg or higher for 3 readings over 3 hours regardless of use of anti-hypertensive drugs or >160/100 mmHg for 3 readings over 3 days on maximum anti-hypertensive drugs; afebrile Grade 4 neutropenia >=7 days or >= Grade 3 neutropenia associated with fever (1 reading of oral temperature >38.5 degree C or 3 readings of oral temperature >38.0 degree C in 24-hour period); Grade 4 thrombocytopenia; hemoptysis of >1/2 teaspoon of bright red blood per day; proteinuria of >=2 grams/24 hours; inability to resume PF-00337210 dosing at current dose level within 14 days of stopping due to treatment-related toxicity; >=Grade 3 nonhematological toxicities (except alopecia and blood pressure/hypertension); Grade 3 nonhematological toxicities that could be controlled to Grade 2 or less with appropriate treatment were not considered dose limiting.	Day 28	Yes
Primary	Maximum Administered Dose (MAD)	MAD: dose level at which 2 or more out of 6 participants experienced DLT during Cycle 1. DLTs: blood pressure of 180/110 mmHg or higher for 3 readings over 3 hours regardless of use of anti-hypertensive drugs or >160/100 mmHg for 3 readings over 3 days on maximum anti-hypertensive drugs; afebrile Grade 4 neutropenia >=7 days or >= Grade 3 neutropenia associated with fever (1 reading of oral temperature >38.5 degree C or 3 readings of oral temperature >38.0 degree C in 24-hour period); Grade 4 thrombocytopenia; hemoptysis of >1/2 teaspoon of bright red blood per day; proteinuria of >=2 grams/24 hours; inability to resume PF-00337210 dosing at current dose level within 14 days of stopping due to treatment-related toxicity; >=Grade 3 nonhematological toxicities (except alopecia and blood pressure/hypertension); Grade 3 nonhematological toxicities that could be controlled to Grade 2 or less with appropriate treatment were not considered dose limiting.	Day 28	Yes
Primary	Recommended Phase-2 Dose (RP2D)	RP2D was determined based on the safety profile and pharmacodynamic findings. The twice daily dosing was preferred over once daily dosing for RP2D, as per investigator's discretion, due to more consistent changes in pharmacodynamic markers and greater clinical benefit observed in twice daily dosing.	Day 28	No
Secondary	Maximum Observed Plasma Concentration (Cmax)		Pre-dose,0.5,1,2,4,6,8,10,16,20,24 hours(hrs) post-dose on Day 1(0.67 mg group);pre-dose,0.5,1,2,4,6,8,18,20,24 hrs post-dose on Day 1,15,29(once daily groups);pre-dose,0.5,1,2,4,6,8 hrs post-dose on Day 1,15,29 (twice daily groups);pre-dose on Day 43, 57	No
Secondary	Plasma Decay Half-Life (t1/2)	Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.	Pre-dose,0.5,1,2,4,6,8,10,16,20,24 hrs post-dose on Day 1(0.67 mg group);pre-dose,0.5,1,2,4,6,8,18,20,24 hrs post-dose on Day 1,15,29(once daily groups);pre-dose,0.5,1,2,4,6,8 hrs post-dose on Day 1,15,29 (twice daily groups);pre-dose on Day 43, 57	No
Secondary	Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-24)]	AUC (0-24)= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-24).	Pre-dose,0.5,1,2,4,6,8,10,16,20,24 hrs post-dose on Day 1(0.67 mg group);pre-dose,0.5,1,2,4,6,8,18,20,24 hrs post-dose on Day 1,15,29(once daily groups);pre-dose,0.5,1,2,4,6,8 hrs post-dose on Day 1,15,29 (twice daily groups);pre-dose on Day 43, 57	No
Secondary	Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - 8)]	AUC (0 - 8)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - 8). It is obtained from AUC (0 - t) plus AUC (t - 8).	Pre-dose,0.5,1,2,4,6,8,10,16,20,24 hrs post-dose on Day 1(0.67 mg group);pre-dose,0.5,1,2,4,6,8,18,20,24 hrs post-dose on Day 1,15,29(once daily groups);pre-dose,0.5,1,2,4,6,8 hrs post-dose on Day 1,15,29 (twice daily groups);pre-dose on Day 43, 57	No
Secondary	Apparent Volume of Distribution (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 plasma concentration of a drug. Apparent volume of distribution after oral dose is influenced by the fraction absorbed.	Pre-dose,0.5,1,2,4,6,8,10,16,20,24 hrs post-dose on Day 1(0.67 mg group);pre-dose,0.5,1,2,4,6,8,18,20,24 hrs post-dose on Day 1,15,29(once daily groups);pre-dose,0.5,1,2,4,6,8 hrs post-dose on Day 1,15,29 (twice daily groups);pre-dose on Day 43, 57	No
Secondary	Systemic Clearance (CL)	CL is a quantitative measure of the rate at which a drug substance is removed from the body.	Pre-dose,0.5,1,2,4,6,8,10,16,20,24 hrs post-dose on Day 1(0.67 mg group);pre-dose,0.5,1,2,4,6,8,18,20,24 hrs post-dose on Day 1,15,29(once daily groups);pre-dose,0.5,1,2,4,6,8 hrs post-dose on Day 1,15,29 (twice daily groups);pre-dose on Day 43, 57	No
Secondary	Number of Participants With Objective Response of Complete Response or Partial Response	Number of participants with objective response based on assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST). Confirmed CR defined as disappearance of all target and non-target lesions and no appearance of new lesions. Confirmed PR defined as at least 30 percent decrease in sum of the longest dimensions (LD) of the target lesions, taking as a reference the baseline sum LD, without progression of non-target lesions and no appearance of new lesions. Confirmed responses are those that persist on repeat imaging study >=4 weeks after initial documentation of response.	Baseline, every 8 weeks up to Cycle 25 (Week 100)	No
Secondary	Change From Baseline in Biomarkers at Day 1 of Each Cycle up to Cycle 25	Biomarkers included soluble plasma proteins associated with angiogenesis (vascular endothelial growth factor [VEGF], soluble vascular endothelial growth factor-2 receptor [sVEGFR2], soluble vascular endothelial growth factor-3 receptor [sVEGFR3], soluble beta type platelet-derived growth factor [sPDGFR beta]) and tumor proliferation (soluble stem-cell factor receptor [sKIT])	Baseline, Day 1 of Cycle 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25	No

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