Study Evaluating Toxicity & Efficacy of Lenalidomide(Revlimid®)in Chemotherapy-Naïve AIPC Patients

A Phase II Study Evaluating the Toxicity and Efficacy of Single Agent Lenalidomide (Revlimid®) in Chemotherapy-Naïve Androgen-Independent Prostate Cancer Patients

This is a single institution, open label, phase II study in androgen-independent prostate cancer patients who are chemotherapy-naïve. Patients will receive Revlimid® 25 mg daily on Days 1-21 followed by 7 days of rest repeated every 28 days. Treatment continues until disease progression, patient's withdrawal, unacceptable toxicity or the investigator's discretion.

The standard of care in patients with androgen independent prostate cancer (AIPC) is debated. Systemic chemotherapy has shown a survival advantage with a Taxotere-based regimen, but this therapeutic approach is associated with significant toxicity and morbidity. Furthermore, some patients with AIPC are asymptomatic with minimal disease burden making systemic chemotherapy a less attractive option. Identifying active agents that are effective in this patient population is of vital importance, as this may delay the need to chemotherapy, palliate symptoms, delay progression, and potentially prolong survival. Acceptable approaches in this setting include vaccine therapies, targeted agents, immunotherapy, or non-taxotere based chemotherapeutic programs. Targeted therapy is of particular interest as this usually avoids side effects of chemotherapy by attacking tumor cells and sparing normal tissue. Ongoing research continues to identify pathways by which the prostate cancer cells become refractory to androgen blockade. During the development of prostate cancer, cell survival depends primarily on the androgen receptor, which is bound to heat shock proteins in the cytoplasm. The active metabolite of testosterone, namely dihydrotestosterone (DHT) binds to the receptor relocating it to the nucleus where it dimerizes, activating transcription genes that are involved in the growth and survival of the cancer cell. Plausible etiologies for the development of hormone resistance and continued cell growth despite adequate castration include changes in antigen receptor expression, changes in the receptor structure, and changes in androgen receptor function with more than one mechanism contributing to this resistance. Several investigators have shown that the androgen receptor gene is the only gene that is consistently up regulated during tumor progression. This increase in androgen receptor mRNA and protein was both necessary and sufficient to convert prostate cancer growth from hormone-sensitive to hormone-refractory, and was dependent on a functional ligand-binding domain. Consequently, one can divide mechanisms of androgen resistance into those that involve the androgen receptor and those that do not.Pathways involving the androgen receptor allow for prostate cancer progression through amplification or mutations of the receptor, deregulation of growth factors or cytokines, and alteration of activators. Amplification of the androgen receptor gene leads to enhanced activation of that receptor even at lower levels of androgens. In addition, mutations in the receptor gene allow for activation of the receptor by different ligands. Peptide growth factors, such as insulin-like growth factor, keratinocyte growth factor, epidermal growth factor, and interleukin-6 (IL 6) can activate the antigen receptor independent of androgens.Deregulation of the apoptotic genes is another important pathway in AIPC development. PTEN tumor suppressor gene (Phosphatase and Tensin Homologue) is mutated in AIPC allowing for the loss of the inhibitory effect that it usually exhibits on the phosphatidylinositol 3-kinase pathway, causing overproduction of akt allowing for cell survival to continue. Another deregulated proapoptotic oncogene, namely bcl-2 allows for cell survival and eventually progression of disease. It has been postulated for years that tumors need an alternative source of nutrients once they outgrow their own supply. Folkman suggested that an angiogenic switch takes place, which accelerates tumor proliferation. Inhibiting tumor proangiogenic factors without affecting normal vasculature has become an attractive theory to inhibit tumor growth. Since prostate cancer, like other malignancies, require blood vessel formation to develop metastases, finding methods that would disrupt this process became of paramount importance. Two separate studies have shown that elevated levels of the vascular endothelial growth factor (VEGF) correspond with advanced stage, progression, and poor survival in prostate cancer. Since VEGF is a major regulator of angiogenesis; a process that is increased in AIPC and since VEGF also correlates with increased microvessel density as well as prognosis, a logical step was to evaluate the activity of VEGF inhibitors and other anti-angiogenesis agents in AIPC. Lenalidomide (Revlimid®) is an analogue of thalidomide that has demonstrated enhanced immunomodulatory properties and a more favorable toxicity profile. The fact that AIPC depends on angiogenesis and lack of appropriate immune reaction to malignant cells and the fact that Revlimid® exhibits its activity by inhibiting angiogenesis with appropriate immunomodulation, makes this agent an attractive option to study in this disease setting.Several investigations suggested activity with thalidomide in AIPC but most studies were in patients who have failed systemic chemotherapy. In addition, Revlimid® has been shown in phase I trials to be safe, less toxic and more tolerable than Thalidomide, with potential activity. This study aims at evaluating the toxicity and efficacy of Revlimid® in AIPC patients who are chemotherapy-naive.

Inclusion Criteria:

1. Understand and voluntarily sign an informed consent form.

2. Age 18 years at the time of signing the informed consent form.

3. Able to adhere to the study visit schedule and other protocol requirements.

4. Documented prostate cancer regardless of Gleason score

5. Patients should be considered hormone refractory and androgen independent. They must fail LHRH analogues, and anti-androgen withdrawal trial. Failure is confirmed by an increase in PSA value of 10% or more than the value immediately before, and confirmed by another assessment 2 weeks later that shows a further increase.

6. Patients must have measurable disease either biochemically (using PSA) and/or using the RECIST criteria for visceral organ involvement and/or bone disease

7. ECOG Performance Status of 2 or less.

8. Adequate liver function tests with ALT/AST being < 3x normal, total bilirubin of 1.5 or less, and adequate renal function measured by a creatinine of 2.0 mg/dl or less. Alkaline phosphatase values are never exclusion criteria if it is deemed related to bone metastases.

9. Patients need to have adequate bone marrow function.

   • ANC of 1000 or above,
   • Hgb of 9.0 g/dl or above,
   • Platelets of 100,000 or above. If other causes are affecting plts counts such as autoimmune disorders, patients are allowed on study. Patients with inadequate bone marrow function that is deemed related to bone marrow involvement with prostate cancer are allowed at the investigator's discretion.

10. Patients with other malignancies are allowed as long as there is no evidence of the other malignancy present at entry time, and it has been 3 years or more since the treatment for the other disorder was completed.

11. Patients with prior exposure to investigational therapies including vaccines are allowed on this study as long as their last exposure was 4 weeks prior to study entry. Erlotinib exposure and GM-CSF is not an exclusion criteria as it is not considered chemotherapy.

12. Patients with known bone metastases are allowed to receive intravenous bisphosphonates such as aredia or zometa. Patients on oral bisphosphonates are also allowed.

13. All study participants must be registered into the mandatory RevAssist® program, and be willing and able to comply with the requirements of RevAssist®.

14. Patients must agree to use a latex condom during sexual contact with a female of childbearing potential, even if they have had a successful vasectomy. See Appendix: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods.

15. Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to ASA may use warfarin or low molecular weight heparin).

Exclusion Criteria:

1. Prior systemic chemotherapy for AIPC. Investigational therapy such as vaccines, immunotherapy, and oral targeted agents such as erlotinib, sorafenib, or sunitinib are allowed.
2. Prior exposure to lenalidomide
3. Known HIV positive status
4. Known brain metastases.
5. Steroids are allowed concomitantly ONLY IF they are taken for another chronic medical condition (Such as COPD, Multiple sclerosis…etc)
6. Presence of other malignancies, unless the last treatment received for any other malignancy was 3 years or more. Non-melanoma skin cancers are excluded.
7. Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form.
8. Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he were to participate in the study or confounds the ability to interpret data from the study.
9. Use of any other experimental drug or therapy within 28 days of baseline.
10. Known hypersensitivity to thalidomide.
11. Known positive for HIV or infectious hepatitis, type A, B or C