ASA404 in Combination With Carboplatin/Paclitaxel/Cetuximab in Treating Patients With Refractory Solid Tumors

Sponsor

University of California, San Francisco (Other)

Overall Status

Withdrawn

CT.gov ID

NCT01031212

Collaborator

Novartis Pharmaceuticals (Industry)

Enrollment

Location

Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This phase I trial is studying the side effects and best dose of an investigational drug called DMXAA (5-6-dimethylxanthenone-4-acetic acid) or ASA404 when given together with carboplatin, paclitaxel and cetuximab to treat patients with refractory solid tumors.

Condition or Disease	Intervention/Treatment	Phase
Tumors	Drug: ASA404 Drug: Cetuximab Drug: Carboplatin Drug: Paclitaxel	Phase 1

Detailed Description

Phase I 3+3 dose escalation design in patients with solid tumors who have been previously treated with chemotherapy or for whom no standard treatment options exist. Carboplatin, paclitaxel and cetuximab will be administered in standard doses. The dose of ASA404 will be escalated under predefined levels. One treatment cycle constitutes 3 weeks. A minimum of 3 patients will be entered at each treatment level, to be expanded to 6 subjects if dose limiting toxicities (DLT) are observed. If no more than one in six patients has DLT, additional patients will be enrolled at a higher dose. Once a maximum tolerated dose (MTD) has been established, the tolerability of this dose will be tested in a total of 12 patients. The anticipated sample size is 18-24 patients.

Carboplatin and paclitaxel are chosen as the chemotherapy back bone since they are commonly used in combination in multiple tumors. Cetuximab has been chosen as the EGFR inhibitor because the combination of platinum based therapy with cetuximab is effective in lung and head and neck cancers. In addition the safety and activity of carboplatin/paclitaxel with ASA 404 has already been demonstrated. A weekly schedule of ASA is chosen because 1) the safety of the weekly schedule has been tested 2) preclinical studies confirm enhanced activity with frequent administration 3) provides an opportunity to evaluate the safety and pharmacokinetics of ASA 404 with weekly cetuximab.

Study Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase I Study of ASA 404 in Combination With Carboplatin/Paclitaxel/Cetuximab in Patients With Refractory Solid Tumors

Study Start Date :

Jan 1, 2010

Anticipated Primary Completion Date :

Jun 1, 2012

Anticipated Study Completion Date :

Jun 1, 2013

Outcome Measures

Primary Outcome Measures

Maximum tolerated dose (MTD) [During cycle 1 (4 weeks)]

Secondary Outcome Measures

The number and percentage of subjects experiencing one or more AEs will be summarized by dose cohort, relationship to study drug, and severity [Within 30 days after study treatment, or until resolution of AE]
Pharmacokinetics of ASA404 in combination with other agents [48 hours after cycle 1, day 1]
Disease response by RECIST criteria [until progression]
Assess biological correlates of antitumor activity by measuring serum 5HIAA, VEGF, bFGF, PLGF, sVEGFR2, FGF 23, serum apoptotic markers (M30/M65) [4 weeks after treatment end]
DNA analysis of FGFR1 and VEGF polymorphism [4 weeks after treatment ends]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histological confirmed malignancy of advanced, incurable solid tumor
Progression following standard therapy, or no acceptable standard treatment options, or eligible if standard therapy consists of a platinum-based doublet
Measurable or evaluable disease. Measurable disease required for enrollment in dose expansion cohort at MTD
ECOG 0-2
Baseline neuropathy grade ≤ 1
leukocytes >3,000/mcL
absolute neutrophil count >1,500/mcL
platelets >100,000/mcL
total bilirubin within normal institutional limits
AST(SGOT)/ALT(SGPT) <1.5 X institutional ULN
creatinine within 1.5 x normal institutional limits OR creatinine clearance >60 mL/min/1.73 m2
Ability to give written informed consent and willingness to comply with requirements of the protocol
Women of child-bearing potential must have a negative pregnancy test within 14 days of beginning study drug and agree to use an effective method of birth control during treatment and for six months after last dose of study drug
Male patients whose sexual partners are women of reproductive potential must be surgically sterile or agree to use a double method of contraception during the study and for six months after last dose of study drug. One of method must be a condom
Patients with known brain metastases should have "stable disease" defined as no growth over a 6 week period after definitive therapy (surgical or RT), and off steroids and anticonvulsive therapy

Exclusion Criteria:

Chemotherapy, hormonal therapy or biologic therapy within 3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to the start of study therapy or not recovered to < grade 2 from adverse events due to prior agents
Prior therapy with EGFR inhibitors is permitted
Patients receiving palliative radiation therapy <2 weeks earlier. Patients must have recovered from all toxicities of radiation
Receiving any other investigational agents
Any severe and/or uncontrolled intercurrent medical conditions or other conditions that could affect participation in the study
Any of the following cardiac abnormalities: unstable angina pectoris, including Prinzmetal variant angina, New York Heart Association (NYHA) Classification for Congestive Heart Failure Grade III or greater, myocardial infarction or stroke ≤ 12 months prior to study treatment, long QT syndrome, baseline 12 lead ECG QTc of

450msec per central evaluation, history of sustained ventricular tachycardia, history of ventricular fibrillation or Torsades de Pointes, right bundle branch block and left anterior hemiblock (bifascicular block), bradycardia (<50 beats per minute)

Concomitant use of drugs with a risk of causing Torsades de Pointes
PT/PTT > 1.5 x ULN
Receiving full-dose anticoagulation (low-dose warfarin for a central line allowed)
History of another primary malignancy less than 5 years prior, except non-melanoma skin cancer or cervical cancer in-situ
Major surgery ≤ 4 weeks prior (requiring general anesthesia or respiratory assistance)(endoscopic exams with diagnostic intent allowed)
Minor surgery ≤ 2 weeks prior (not requiring general anesthesia or respiratory assistance)
Insertion of vascular access device allowed
Not recovered from surgery-related complications
Systolic BP >160mmHg and/or diastolic BP >90mmHg while on medication for hypertension
Hemoptysis associated with chest malignancy <4 weeks (>1 teaspoon)
History of hypersensitivity reactions to TAXOL or other drugs formulated in Cremophor® EL (polyoxyethylated castor oil)
History of severe allergic reactions to cisplatin or other platinum-containing compounds
History of acute hemorrhagic events requiring hospital admission or blood transfusion
Pregnant or lactating women
Fertile women and men not willing to comply with birth control instructions
Any condition that compromises compliance with objectives and procedures of this protocol, as judged by the principal investigator