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

Phase 1
18 Years
Not Enrolling

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Trial Information

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

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.

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

- 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

- 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

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose (MTD)

Outcome Time Frame:

During cycle 1 (4 weeks)

Safety Issue:


Principal Investigator

Sarita Dubey, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of California, San Francisco


United States: Food and Drug Administration

Study ID:




Start Date:

January 2010

Completion Date:

June 2013

Related Keywords:

  • Tumors
  • cancer
  • neoplasms
  • adult solid tumor
  • antineoplastic agents



UCSF Helen Diller Family Comprehensive Cancer Center San Francisco, California  94115