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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

Phase 1
18 Years
Not Enrolling

Thank you

Trial Information

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

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

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.

Inclusion Criteria

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

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

15. Inability to comply with protocol requirements

Type of Study:


Study Design:

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

Outcome Measure:

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)

Outcome Time Frame:

one year

Safety Issue:


Principal Investigator

Manuel Hidalgo, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Johns Hopkins University


United States: Food and Drug Administration

Study ID:




Start Date:

October 2006

Completion Date:

February 2010

Related Keywords:

  • Tumor
  • Solid Tumors
  • Tyrosine Kinases



Johns Hopkins University School of Medicine Baltimore, Maryland  21205