Official Title: “A Phase 1, Sequential Cohort, Dose Escalation Trial to Determine the Safety, Tolerability, and Maximum Tolerated Dose of Daily Oral Administration of AV-412 in Patients With Refractory or Relapsed Solid Tumor Malignancies”

AV-412 is a new oral therapy developed to inhibit the growth of solid tumors in patients who have not responded to standard therapy or surgical interventions, or who have experienced relapse. This study will test the safety of AV-412 and determine the maximum tolerated dose for the treatment of solid tumors.

Study Type: Interventional

Study Design: Treatment, Non-Randomized, Open Label, Uncontrolled, Single Group Assignment, Safety Study

Study Primary Completion Date: December 2008

Although progress has been made, patients with malignancies often either progress after the traditional approach of chemotherapy, surgery, or radiotherapy, or are not candidates for these approaches because of the advances stage of disease. Novel therapies that may offer greater potential than those currently available are urgently needed.

AV 412 is a potent inhibitor of human epidermal growth factor family receptor tyrosine kinases (TKIs) and represents a growing class of anti-cancer agents. The recent introduction of TKIs has opened the door to new approaches to cancer treatment in which the goals of therapy are to halt disease progression, ameliorate symptoms, and improve patient quality of life. AV412 may inhibit growth of solid tumors, with fewer and less debilitating side effects.

This study is designed to determine the safety, tolerability and maximum tolerated dose of daily oral administration of AV 412. Patients will be assigned to escalating drug dose cohorts to determine the optimal dose. Evaluations to determine tolerability include PK, PD, and the adverse events which occur during the course of study drug administration.

Intervention(s) in this Clinical Trial

• Drug: AV-412
  • Solid oral dosage; 4 dosage strengths; 25, 50, 100, or 200 mg per capsule Dosing Frequency: Once daily dosing for 4 weeks (4 weeks equals 1 cycle)

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: A
  • Daily oral administration of AV-412

Primary Measures

• To evaluate the safety, tolerability, and dose-limiting toxicities (DLT), and determine the maximum tolerated dose (MTD) of AV-412 when administered once daily by the oral route for 4 weeks (4 weeks equals one dosing cycle)
  • Time Frame: one year
    Safety Issue?: Yes

Secondary Measures

• To characterize the pharmacokinetic (PK) profile of AV-412 in all patients. Extensive PK collection and assay to be performed in expanded MTD Cohorts
  • Time Frame: 18 months
    Safety Issue?: Yes
• Evaluate potential pharmacodynamic (PD) markers of AV-412 action, in expanded MTD Cohorts ONLY
  • Time Frame: two years
    Safety Issue?: No
• Preliminary evaluation of the antineoplastic activity of AV-412 (assessed by evidence and duration of disease stabilization or objective response, and time to disease progression)
  • Time Frame: two years
    Safety Issue?: No

Criteria for Inclusion:

• 1. ≥ 18 year old males or females
• 2. Documented measurable or evaluable solid tumor malignancy that is relapsed, refractory, locally advanced, or metastatic
• 3. Patients entered to MTD Cohort B must have:
• Histologically or cytologically confirmed NSCLC
• No prior therapy with erlotinib, gefitinib, or any other EGFR-kinase inhibitor
• Previously documented exon 19 deletion and/or exon 21 L858R mutations
• Measurable disease according to RECIST
• 4. Disease that is currently refractory to, or not amenable to, standard therapy
• 5. Disease that is currently not amenable to surgical intervention, due to either medical contraindications or nonresectability of the tumor
• 6. Karnofsky performance status ≥ 70%, life expectancy ≥ 3 months
• 7. No childbearing potential or use of effective contraception by all fertile male and female patients, during the study and for 3 months after the last dose of study drug
• 8. Ability to give written informed consent

Criteria for Exclusion:

• 1. Pregnant or lactating women
• 2. Primary CNS malignancies; active CNS metastases
• 3. Hematologic malignancies (includes: leukemia, any form; lymphoma; and multiple myeloma)
• 4. Active second malignancy or history of another malignancy within 2 years with the exception of:
• Treated, non-melanoma skin cancers
• Treated CIS of the breast or cervix
• Controlled, superficial bladder carcinoma
• T1a or b prostate carcinoma involving < 5% of resected tissue and PSA within normal limits (WNL)
• 5. Any of the following hematologic abnormalities:
• Hemoglobin ≤ 9.0 g/dL
• ANC < 1,500 per mm3
• Platelet count < 100,000 per mm3
• 6. Any of the following serum chemistry abnormalities:
• Total bilirubin > 1.5 × the ULN
• AST or ALT ≥ 3 × the ULN (≥ 5 × if due to hepatic involvement by tumor)
• Serum albumin < 2.5 g/dL
• Creatinine ≥ 1.5 × ULN (or calculated CLCR < 50 mL/min/1.73 m2)
• 7. Significant cardiovascular disease, including:
• CHF requiring therapy
• Ventricular arrhythmia requiring therapy
• Any conduction disturbance (including patients with QTc interval prolongation >
• 0.47 sec, history of a severe arrhythmia, or history of a familial arrhythmia
• [eg, WPW])
• Angina pectoris requiring therapy
• LVEF < 50% by MUGA or Echocardiogram
• Uncontrolled HTN
• MI within 6 months of study entry
• NYHA > Class I
• 8. Significant gastrointestinal abnormalities, including:
• Requirement for IV alimentation
• Prior surgical procedures affecting absorption
• Active peptic ulcer disease
• ≥Grade 2 diarrhea due to any etiology
• 9. Known history of significant ophthalmologic abnormalities, including:
• Severe dry-eye syndrome
• Keratoconjunctivitis sicca
• Sjogren's syndrome
• Severe exposure keratopathy
• Disorders increasing risk for epithelium-related complications
• 10. Serious/active infection; infection requiring parenteral antibiotics
• 11. Inadequate recovery from prior antineoplastic therapy
• 12. Inadequate recovery from any prior surgical procedure; major surgical procedure within 2 weeks
• 13. Life-threatening illness or organ system dysfunction compromising safety evaluation
• 14. Psychiatric disorder, altered mental status precluding informed consent or necessary testing
• 15. Inability to comply with protocol requirements

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: AVEO Pharmaceuticals, Inc.

Overall Clinical Trial Officials and Contacts

Manuel Hidalgo, MD, PhD Principal Investigator Johns Hopkins University  

Overall Contact: Debra L Wood, MD (973) 989-5010 dlwoodmd@aol.com

Information obtained from ClinicalTrials.gov on October 10, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00381654

Study ID Number: AV-412-06-101

ClinicalTrials.gov Identifier: NCT00381654

Health Authority: United States: Food and Drug Administration

Aveo Pharmaceutical, Inc home page