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1. A PHASE I STUDY OF AUTOLGOUS BONE MARROW TRANSPLANTATION WITH STEM CELL GENE MARKING IN MULTIPLE MYELOMA.

2. A PHASE I/II STUDY OF MDR-1 CHEMOPROTECTION IN METASTATIC BREAST CANCER.

3. A PHASE I STUDY OF ADENOVIRUS MEDIATED GENE TRANSFER OF INTERLEUKIN 2CDNA INTO METASTATIC BREAST CANCER OR MELANOMA.

4. AUTOLOGOUS GENE MODIFIED PLASMA CELL VACCINATION FOLLOWING PERIPHERAL BLOOD STEM CELL TRANSPLANTATION FOR THE CONTROL OF MINIMAL RESIDUAL MYELOMA.

5. A PHASE I STUDY OF ADENOVIRUS MEDIATED GENE TRANSFER OF INTERLEUKIN 2 cDNA INTO LOCALLY ADVANCED ADENOCARCINOMA OF THE PROSTATE

6. A PHASE II TRIAL OF SCH 58500 IN COMBINATION WITH CHEMOTHERAPY FOR THE TREATMENT OF NON-SMALL CELL LUNG CANCER

Study Outline:

Objectives of the Trial

b) To assess short-term and long-term in vivo reconstituting capacity of infused autologous marrow progenitors activated in LTMCs.

c) To evaluate the potential of transduced, autologous, LTMC-derived hematopoietic progenitor cells as vehicles for cancer gene therapy.

Contact Person:

Dr. A.K. Stewart, Phone (416) 340-3965 / Fax (416) 340-3220
The Toronto Hospital (General Division) -2MLW-024
657 University Avenue, Toronto, ON - M5G 2C4

Inclusion Criteria

1. Ages <65 years at the time of pre-transplant evaluation.
2. Multiple myeloma (Durie Salmon stage II or III).
3. Ineligible for randomized study of myeloablative versus standard therapy.
4. Performance status of 0 or 1 and a life expectancy of >3 months.
5. Normal pulmonary, cardiac and renal function.
6. Ability to provide informed consent to all aspects of the trial.
7. No previous radiotherapy to the thoracic spine (>2000 rads) or lung (10cm2).

Clinical Endpoints:

• Autograft viability following LTMC - (residual erythroid and granulocyte/macrophage colony forming units, nucleated cells counts and CD34+ progenitor cell content).
  
• Autograft sterility following LTMC (bacteria, fungi, mycoplasma).
• Potential acute toxicity associated with LTMX infusion (NIH-CTC)
• Other short term toxicity (NIH-CTC).
• Infection related morbidity and mortality.
• Days to absolute neutrophil count >0.5 x 109/L
• Days to platelet count of 20 x 109/L
• Time to transfusion independence.
• Absence of replication competent retrovirus (LTMC will be tested prior to infusion and patient serum tested every three months following infusion for two years).
• Long term toxicity (e.g., development of second malignancy).

Study Outline:

In this phase I/II clinical trial bone marrow (1.5 x 108 nucleated cells/kg) will be harvested from each of 16 volunteer patients with metastatic breast cancer. These bone marrow cells will be used to initiate long-term marrow cultures (LTMCs). Hematopoietic stem cells in the LTMC will be transduced with a replication incompetent retroviral vector (A12M1) bearing the human multi-drug resistance (MDR-1) gene. After 3 weeks of culture the LTMC cells will be cryopreserved and aliquots will be distributed for safety testing. While the three week LTMC and subsequent safety testing is underway patients will begin chemotherapy with Cyclophosphamide, Adriamycin and 5-Fluorouracil (CAF). The dose of Cyclophosphamide will be escalated and G-CSF will be employed to allow harvesting of peripheral blood stem cells for cryopreservation. Following stem cell collection patients will receive a single dose of Taxol at standard dose. Safety testing will be complete by the time of recovery from Taxol and patients will be next randomized to high dose or escalating dose chemotherapy.

Objectives of the Trial

b) To document the short and long term engraftment of MDR-1 transduced LTMC cells.

c) To compare engraftment of gene marked LTMC cells in conditioned and unconditioned recipients.

d)To study the ability of Taxol chemotherapy to select for bone marrow cells carrying the transduced MDR-1 gene in vivo.

e)To evaluate the ability of MDR-1 expressing bone marrow cells to abrogate the myelosuppression of chemotherapy agents.

Contact Person:

Inclusion Criteria

1. Metastatic breast cancer.
2. No morphologic or immunohistochemical evidence for marrow involvement by breast cancer.
3. Normal serum Calcium
4. Ability to provide informed consent to all aspects of the trial.
5. No more than two prior chemotherapy regimens for metastatic breast cancer.
6. Life expectancy greater than six months.

Exclusion Criteria

1. HIV/HTLV-1 infection
2. Inability to return to Toronto for regular follow up appointments.
3. Pregnancy.
4. Ejection fraction <45%. Previous myocardial infarction within one year.
5. Angina or hypertension uncontrolled by medication.
6. Inadequate pulmonary reserve defined as FEV1 or DLCO less than 50 % normal.
7. Abnormal blood counts (Hgb <100g/l, WBC <3.5 x 109/L, Plt <150 x 109/L)
8. Brain metastasis.
9. ECOG performance status >2.
10. History of secondary malignancy.
11. Prior history of myelodysplasia, abnormal marrow morphology, marrow cytogenetic change.

Clinical Endpoints:

• Successful short term engraftment of hematopoietic cells in myeloablated patients.
• Toxicity associated with LTMC infusion (CTC criteria)
• Other short term toxicity (CTC criteria)
• Long term toxicity i.e. development of second malignancy
• The myeloprotective effect of MDR-1 expression after Taxol or high dose therapy

Biologic Endpoints

• Evaluation of in vitro gene transfer efficiency.
• Gene transfer and expression in vivo.
• Interpretation of results.

Study Outline:

Clinical endpoints

Contact Person:

Inclusion Criteria

1. Documented metastatic disease with easily accessible tumor deposits (skin nodules or lymph nodes are preferred but are not an absolute requirement).
2. Metastatic melanoma.
3. Hormone and chemotherapy resistant metastatic breast cancer.
4. Breast cancer patients eligible for chemotherapy must have failed at least one regimen. Melanoma patients need not be previously treated.
5. Performance status of 0 - 2 and a life expectancy of > 3 months.
6. Ability to provide informed consent to all aspects of the trial.
7. No chemotherapy or radiotherapy within four weeks of injection.
8. Measurable disease.

Exclusion Criteria

1. HIV or HTLV I infection.
2. Patient found to be shedding adenovirus on pre-study cultures.
3. Inability to return to Toronto for regular follow up appointments.
4. Pregnancy, nursing mother or refusal and/or inability to use adequate contraception during the six months following the trial.
5. Total WBC, neutrophil, or absolute lymphocytes below normal value. CD4 <200 or CD8 <100.
6. Quantitative serum immunoglobulins below institutional normal.
7. Ongoing treatment or likely need for treatment with corticosteroids. It should be noted that this requirement does not preclude the use of steroids in compelling circumstances (e.g. spinal cord compression, brain metastasis) which may arise after the AdCAIL-2 injection.
8. Persistent angina, congestive heart failure or history of myocardial infarction within the previous year.
9. Creatinine greater than twice institutional normal level.
10. Inadequate pulmonary reserve defined as FEV1 or DLCO less than 50 % normal.

Study Outline:

Objectives of the Trial

1. In a phase 1 study to vaccinate myeloma patients with autologous irradiated malignant plasma cells genetically engineered by adenoviral vectors to express the immune stimulatory molecule Interleukin-2
2. To monitor safety and toxicity of this approach.
3. To serially immunize patients and observe for an in vitro and in vivo biologic response.

Contact Person:

e mail: Dr. A.K. Stewart

Inclusion Criteria

1. Confirmed diagnosis of Durie-Salmon stage 111 multiple myeloma
2. Age <70
3. Performance status of 0-2 and a life expectancy of <3 months.
4. Ability to provide informed consent to all aspects of the trial
5. Measurable disease as defined by quantifiable serum or urine paraprotein at diagnosis.
6. Chemosensitive or stable myeloma prior to stem cell mobilization.
7. No chemotherapy or radiotherapy within four weeks of injection. Total WBC count >2 x 10⁹/L at time of vaccination.

Exclusion Criteria

1. HIV infection.
2. Inability to return to Toronto for regular follow up appointments.
3. Pregnancy, nursing mother or refusal and/or inability to use adequate contraception during three months following the trial.
4. Persistent angina, congestive heart failure or history of myocardial infarction within past year.
5. Inadequate pulmonary reserve defined as FEV1 or DLCO less than 50 % normal.
6. Non secretory myeloma.
7. Progressive disease.
8. History of allergy to mice. History of anaphylaxis in response to Iron containing products.

Clinical Endpoints:

• Acute local toxicity of virus injection.
• Acute systemic toxicity of virus injection
• Local tumor response.
• Systemic tumor response.
• Chronic toxicity of virus injection.
• Time to absence of replication competent virus.

Biologic Endpoints:

Absence of infectious virus. Evidence for anti-adenovirus antibody response. Evidence for enhanced lymphocyte proliferation in response to autologous parental Myeloma cells.

Study Outline:

Objectives of the Trial

1. To establish the maximum tolerated and/or optimal biologic dose of AdCAIL-2 in a phase I dose escalation.
2. In ancillary laboratory studies to establish the presence or absence of: i) an antibody response to adenovirus, ii) replication competent adenovirus and iii) increased levels of local and circulating IL-2.
3. To determine the local and systemic response rates obtained in patients treated with AdCAIL-2.

Contact Person:

:

Inclusion criteria

1. Documented localized prostate cancer with poor prognosis for cure and easily
   accessible tumor deposits appropriate for treatment by radical prostatectomy i.e. T2 lesions,
   and T1c with positive biopsies from both lobes
2. Increased risk of post operative recurrence based on a) both of the following criteria:
   preoperative PSA equal or greater than 10 mg/mL, and Gleason score of 7 or b) Gleason score greater than 7, 9 or 9.
3. No previous anticancer treatment
4. Performance status of 0 - 2 and a life expectancy of > 3 months
5. Ability to provide informed consent to all aspects of the trial
6. No chemotherapy or radiotherapy or hormonal therapy within four weeks of injection.
7. Measurable disease.

Exclusion criteria

1. HIV or HTLV I infection.
2. Patient found to be shedding adenovirus on pre-study cultures.
3. Inability to return to Toronto for regular follow up appointments.
4. Refusal / inability to use adequate contraception during the six months following the trial.
5. Total WBC count, neutrophil count, below institutional normal value. Absolute CD4 lymphocyte count <200 or CD8 count <100.
6. Quantitative serum immunoglobulins below institutional normal.
7. Ongoing treatment or likely need for treatment with corticosteroids.
8. Persistent angina, congestive heart failure or history of myocardial infarction within the previous year.
9. Creatinine greater than twice institutional normal level.
10. Inadequate pulmonary reserve defined as FEV1 or DLCO less than 50 % normal.
11. Active autoimmune disorder or immunodeficiency syndrome.

Clinical endpoints

1. Acute local toxicity of virus injection.
2. Acute systemic toxicity of virus injection.
3. Local tumor response.
4. Chronic toxicity of virus injection.
5. Time to absence of replication competent virus.

For More Information on the specifics of this trail please contact one of the investigators listed below.

Contact:

Dr. A.K. Stewart, Phone (416) 340-3965 / Fax (416) 340-3220
The Toronto Hospital (General Division) -2MLW-024
657 University Avenue, Toronto, ON - M5G 2C4

e mail: Dr. A.K. Stewart

Dr. J. Dancey, Phone (416) 340-4263 / Fax (416) 340-3220
The Toronto Hospital (General Division) -2MLW-031
657 University Avenue, Toronto, ON - M5G 2C4

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Last revised: Dec 30/97