To Immunize Pts w Extensive Stage SCLC Combined w Chemo w or w/oAll Trans Retinoic Acid

Condition(s) targeted: Small Cell Lung Cancer

Intervention: Observation (Other); Drug: Ad.p53-DC vaccines (Biological); Ad.p53-DC vaccines + ATRA (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: H. Lee Moffitt Cancer Center and Research Institute

Official(s) and/or principal investigator(s):
Alberto Chiappori, M.D., Principal Investigator, Affiliation: H. Lee Moffitt Cancer Center and Research Institute

Overall contact:
Alberto Chiappori, M.D., Phone: 813-745-2158, Email: alberto.chiappori@moffitt.ofg

The purpose of this research study is to test a tumor (cancer) vaccine given along with chemotherapy to determine if this vaccine will increase the amount of time that people who have this disease will live. The vaccine will be made by inserting a gene (p53 gene) into a subset of the patient's own white blood cells. The vaccine will be given after the patient receives standard first-line chemotherapy, and may be given after second-line chemotherapy. One third of the people involved in the study will also be given a medication called All Trans Retinoic Acid (ATRA).

Official title: A Randomized Phase II Trial Using Dendritic Cells Transduced With an Adenoviral Vector Containing the p53 Gene to Immunize Patients With Extensive Stage Small Cell Lung Cancer in Combination With Chemotherapy With or Without All Trans Retinoic Acid

Study design: Treatment, Randomized, Open Label, Factorial Assignment, Safety/Efficacy Study

Primary outcome: To evaluate the efficacy of the combination of the Ad.p53-DC vaccine, with (Arm C) and without (Arm B) ATRA, and subsequent chemotherapy (paclitaxel). That is, to estimate the objective tumor response rate for each treatment group.

Secondary outcome: To evaluate the survival of all patients enrolled on an intent-to-treat basis, with a comparison made between the 3 arms.

Detailed description: TREATMENT PLAN:

- First-line Chemotherapy

After initial diagnosis patients will be treated with a standard platinum/etoposide regimen. This standard chemotherapy may be administered to patients under the direction of their primary medical oncologist outside of the Moffitt Cancer Center. Patients will receive platinum-based chemotherapy on day 1 and etoposide on days 1-3 of each 21-day cycle. Pre-medications for the platinum-based therapy on day 1 are: ondansetron 16mg PO 30 minutes prior to chemotherapy, dexamethasone 20mg IVPB over 30 minutes prior to chemotherapy, and lorazepam 1mg IVP over 1-3 minutes prior to chemotherapy. No pre-medications are necessary for the etoposide infusions on days 2 and 3, and the etoposide is given the same way that it was given on day 1. The radiographic studies and tumor measurements are repeated just prior to beginning the third cycle. Patients who have progressive disease at this point are changed to second line chemotherapy, and will not receive any further protocol treatment. Patients who achieve a CR, PR, or SD go on to receive 2 to 4 more cycles of the platinum/etoposide regimen at the discretion of the treating oncologist. Radiographic studies and tumor measurements are repeated 3 weeks after the last dose of chemotherapy.

Analgesics, megestrol acetate, erythropoietin, antidepressants, and other supportive care measures may be used at the investigator's discretion. If a patient develops grade 4 neutropenia, febrile neutropenia, or prolonged neutropenia, G-CSF injections may be used during subsequent cycles of chemotherapy.

- Randomization Procedure

Patients who successfully complete the screening exams for initial registration will be randomized into one of three study arms. The study Biostatistician will generate a Flow Chart for Randomization. This Flow Chart will be held in confidence by the Biostatistician and the Immunotherapy Regulatory Coordinator. The individual randomization assignment will be released by the Regulatory Coordinator only after the first patient signs the informed consent document and successfully completes the screening process.

- Treatment of Patients on Arm A

Those patients randomized to the control Arm A will be observed with physical examinations, laboratory work, serial CT scans and immune blood testing every 3 months. At the time of disease progression they will receive second-line chemotherapy with paclitaxel.

- Treatment of Patients on Arm B

Those patients randomized to Arm B will receive vaccinations on 3 occasions, at 2 week intervals. 5x10 6 p53 positive DCs in 1 ml will be injected intradermally into 4 separate sites (0. 25 ml injected at each site), in bilateral proximal upper and lower extremities (in the regions of the axillary and inguinal nodal basins). Patients will be restaged approximately 2 weeks after vaccine #3. If patients show no sign of disease progression at restaging, then a second leukopheresis will be performed. Patients will then be vaccinated three more times at 4-week intervals, for a total of 6 possible vaccines.

- Treatment of Patients on Arm C

The patients in Arm C will receive vaccines at the same dose and schedule as described for patients in Arm B. In addition they will receive 150 mg/m2 of ATRA for 3 days prior to each vaccine administration (followed by administration of the vaccine the fourth day). This is based on our preliminary data that demonstrate a persistence of the ATRA effect on ImC for a

minimum of 2 weeks. Note - for patients on ARMs B and C: the use of steroid medication is to

be avoided for 4 weeks prior to the initiation of vaccine therapy and during the vaccine treatment period.

- Second-line Chemotherapy

At any point when a patient develops evidence of progressive disease, the patient will be treated with second-line chemotherapy. Paclitaxel will be given at a dose of 225 mg/m2 on day 1 of 21 day cycles. Standard pre-medications to avoid emesis and hypersensitivity reactions will be administered: dexamethasone 20mg po 7 and 14 hours prior to paclitaxel or dexamethasone 20mg IV, plus, diphenhydramine 50mg IV and ranitidine 50mg 30 minutes prior to paclitaxel.

For any Grade 3 or higher toxicity, the dose of paclitaxel will be reduced the first time to 200 mg/m2. Further reductions will be at the discretion of the treating physician in consultation with the Principal Investigator. No more than 2 dose reductions for paclitaxel will be allowed. Growth factor support is permitted per ASCO guidelines.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria at the time of initial registration:

- Must have a histologically confirmed diagnosis of SCLC.

- Must have extensive stage SCLC and/or lesions that have spread to other tissues in the

chest or other parts of the body.

- Must have completed first line chemotherapy: 4-6 cycles of a standard

platinum/etoposide regimen.

- ECOG performance status of 0-2.

- Adequate organ function including:

1. WBC > 3,000/mm³ and ANC > 1500/ mm³

2. Platelets > 100,000/ mm³

3. Hematocrit > 25%

4. Hemoglobin ≥10g/dl

5. Bilirubin < 2. 0 mg/dl

6. Creatinine < 2. 0 mg/dl

7. AST/SGOT ≤2 x ULN

8. Alkaline phosphatase ≤3 x ULN

- Tumor Assessment: SD, PR, or CR assessed 3 weeks after the last cycle of first line

chemotherapy

- Males and Females of reproductive potential must agree to use effective contraception

during the study and for at least 4 weeks after the last dose of ATRA. Patients are instructed and agree to notify the principal investigator should a pregnancy occur for themselves or their partner.

- Must be willing and able to sign written informed consent and be able to comply with

the study protocol for the duration of the study.

Inclusion Criteria just prior to treatment with vaccines:

- Must have had a successful harvest of PBMC with leukapheresis at least 6 weeks after

chemotherapy.

- ECOG performance status must be 0-2.

- The last dose of first line chemotherapy must have been administered at least 4 weeks

prior to the first vaccine administration.

- For patients who received radiation therapy, the last dose of radiation must have been

completed at least 4 weeks prior to the first vaccine administration and the patient must have recovered from the toxic effects of the treatment prior to study enrollment (except for alopecia).

- For patients who received steroid therapy, the last steroid dose must have been given

at least 4 weeks prior to the first vaccine administration

- Adequate organ function:

1. WBC > 3,000/mm³ and ANC > 1500/ mm³

2. Platelets > 100,000/ mm³

3. Hematocrit > 25%

4. Hemoglobin ≥10g/dl

5. Bilirubin < 2. 0 mg/dl

6. Creatinine < 2. 0 mg/dl

7. AST/SGOT ≤ 2 x ULN

8. Alkaline phosphatase < 3 x ULN

- Patients must have signed informed consent at initial registration.

- HLA-A*0201 Testing as determined by flow cytometry followed by molecular analysis of a

peripheral blood specimen, however this result will not be an inclusion criterion

Exclusion Criteria at the time of initial registration:

- Severe, uncontrolled intercurrent illness or infection.

- Anticipated requirement for chronic steroid use at the time of vaccination.

- Any pre-existing immunodeficiency condition, or a known history of HIV, Hepatitis B or

Hepatitis C.

- Uncontrolled CNS metastasis will not be permitted.

- Pregnant or lactating women. A pregnancy test-serum BHCG will be obtained during the

screening process.

- Patients who have received any chemotherapy other than the first line chemotherapy

specified in the study protocol: standard platinum/etoposide regimen.

- Patients who have received any prior investigational drugs including immunotherapy,

gene therapy, hormone therapy, biologic therapy for treatment of SCLC.

- Any known pre-existing autoimmune disorder.

- History of a second malignancy within the previous 5 years (except non-melanoma skin

cancer and cervical in-situ).

- Patients who have not recovered from any chemotherapy-related or other therapy-related

toxicity at study entry.

- Patients who have had major surgery without full recovery or major surgery within

three weeks of the start of vaccine treatment.

- Patients with other significant diseases or disorders that, in the Investigator's

opinion, would exclude them from the study

Exclusion Criteria for vaccine registration:

- Uncontrolled brain metastasis.

- Ongoing steroid use or the anticipated requirement for steroid use during the

treatment period.

- ECOG performance status of 3 or 4.

- Any serious ongoing infection.

- Patients who have had major surgery within 3 weeks of the start of vaccine treatment.

Alberto Chiappori, M.D., Phone: 813-745-2158, Email: alberto.chiappori@moffitt.ofg

H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, United States; Recruiting
Alberto Chiappori, M.D., Phone: 813-745-2158, Email: alberto.chiappori@moffitt.org
Robin Szekely, Phone: 813-745-7280, Email: robin.szekely@moffitt.org
Alberto Chiappori, M.D., Principal Investigator
Gerold Bepler, M.D., PhD., Sub-Investigator
Eric Haura, M.D., Sub-Investigator
William Janssen, PhD., Sub-Investigator
George Simon, M.D., Principal Investigator
Tawee Tanvetyanon, M.D., Sub-Investigator
Charles Williams, M.D., Sub-Investigator
Soner Altiok, M.B., PhD., Sub-Investigator
Jhannell Gray, M.D., Sub-Investigator

Moffitt Cancer Center Clinical Trials website

Starting date: October 2007
Ending date: October 2012
Last updated: July 1, 2008