investigator letter from drug manufacturer stating animal studies showed increased risk of cancer which was an unknown adverse event

The purpose of this study it to evaluate the efficacy of PTK787/ZK 222584, in inducing at least a 50% reduction in paraprotein in patients with multiple myeloma whose paraprotein levels are < 5 g/dL following high dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT).

To evaluate the efficacy of PTK787/ZK 222584, in inducing at least a 50% reduction in paraprotein in patients with multiple myeloma whose paraprotein levels are < 5 g/dL following high dose chemotherapy (HDCT) and Autologous Stem Cell Transplantation (ASCT).

To assess the time to progression and disease free survival of patients treated with PTK787/ZK 222584.

To assess the safety and tolerability of PTK787/ZK 222584 in multiple myeloma patients following ASCT.

Inclusion Criteria:

• Patients eligible for this trial are those diagnosed with multiple myeloma by standard criteria and treated with HDCT and ASCT on protocols at Washington University School of Medicine. Following HDCT and ASCT patients must have:

  1. M-component (IgG or IgA) with persistent measurable paraprotein, or >=2 g monoclonal protein in 24 hr urine specimen or patients with an abnormal serum kappa/lambda ratio and a level of kappa or lambda light chain > 10 mg/dl.

  2. >=90 days and <= 120 days post transplant

  3. Laboratory values less than or equal to 2 weeks prior to initiation of treatment:

     • Absolute neutrophil count (ANC) greater than or equal 1.5 x 10^9/L
     • Platelets (PLT) greater than or equal to 100 x 10^9/L
     • Hemoglobin (Hgb) greater than or equal to 9 g/dL
     • Serum creatinine less than or equal to 1.5 upper limit of normal (ULN)
     • Serum bilirubin less than or equal to 1.5 ULN
     • Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) less than or equal to 3.0 x ULN
     • Negative for proteinuria based on dip stick reading OR, if documentation of +1 result for protein on dip stick reading, then total urinary albumin ≤ 500 mg and measured creatinine clearance (CrCl) greater than or equal to 50 mL/min from a 24-hour urine collection

  4. A negative pregnancy test 48 hours prior to study treatment and must not be lactating if they are females of childbearing age.

  5. Ability to understand and the willingness to sign a written informed consent document in accordance with the guidelines of the Washington University Human Studies Committee.

  6. Age greater than or equal to 18 years old.

  7. ECOG performance status less than or equal to 2.

Exclusion Criteria:

1. Receiving any other investigational agents.

2. Receiving concurrent steroids with a dose equivalent of prednisone of >= 150 mg/month.

3. Female patients who are pregnant or breast feeding, or adults of reproductive potential not employing an effective method of birth control. Barrier contraceptives must be used throughout the trial in both sexes. Oral, implantable, or injectable contraceptives may be affected by cytochrome P450 interactions, and are therefore not considered effective for this study.

4. Biopsy proven amyloidosis.

5. Patients with a history of another primary malignancy within less than or equal to 5 years, with the exception of inactive basal or squamous cell carcinoma of the skin.

6. Prior chemotherapy less than or equal to 3 weeks prior to registration and/or randomization. Patients must have recovered from all therapy-related toxicities.

7. Prior biologic or immunotherapy less than or equal to 2 weeks prior to registration and/or randomization. Patients must have recovered from all therapy-related toxicities.

8. Prior full field radiotherapy less than or equal to 4 weeks or limited field radiotherapy less than or equal to 2 weeks prior to randomization. Patients must have recovered from all therapy-related toxicities.

9. Pleural effusion or ascites that cause respiratory compromise (greater than or equal to CTC grade 2 dyspnea).

10. Major surgery (i.e. laparotomy) less than or equal to 4 weeks prior to randomization. Minor surgery less than or equal to 2 weeks prior to randomization. Insertion of a vascular access device is not considered major or minor surgery in this regard. Patients must have recovered from all surgery-related toxicities.

11. Patients who have received investigational drugs less than or equal to 4 weeks prior to registration and/or randomization.

12. Prior therapy with anti-vascular endothelial growth factor (VEGF) agents.

13. Any of the following concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study:

    • Uncontrolled high blood pressure, history of labile hypertension, or history of poor compliance with an antihypertensive regimen
    • Unstable angina pectoris
    • Symptomatic congestive heart failure
    • Myocardial infarction less than or equal to 6 months prior to registration and/or randomization
    • Serious uncontrolled cardiac arrhythmia
    • QTc interval > 450 milliseconds in males or > 470 milliseconds in females Uncontrolled diabetes
    • Active or uncontrolled infection
    • Interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the lung

14. Acute or chronic liver disease (e.g. hepatitis, cirrhosis).

15. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of PTK787/ZK 222584 (i.e., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, bowel obstruction, or inability to swallow the tablets).

16. Patients with confirmed diagnosis of human immunodeficiency virus (HIV) infection are excluded at the investigator's discretion if he/she feels that: a potential drug interaction between PTK787/ZK 222584 and any of the patient's anti-HIV medications could influence the efficacy of the anti-HIV medication, or it may place the patient at risk due to the pharmacologic activity of PTK787/ZK 222584.

17. Patients who are taking therapeutic warfarin sodium (Coumadin) or similar oral anticoagulants that are metabolized by the cytochrome P450 system. Heparin is allowed.

18. Patients unwilling to or unable to comply with the protocol.

Adverse events were collected from the start of treatment up through 30 days following the end of treatment.

In November 2008, it was reported that the drug might have carcinogenic potential in animal models. At that time, the remaining three patients were taken off study.