A Pilot Study to Determine the Safety and Tolerability of Sirolimus Given With Hyper-CVAD Chemotherapy

A Pilot Study of Hyperfractionated Cyclophosphamide, Vincristine, Doxorubicin, and Dexamethasone (Hyper-CVAD) With Sirolimus for the Treatment of Adult Acute Lymphoblastic Leukemia and Aggressive Lymphoid Malignancies

This is a pilot study, assessing the feasibility, safety and toxicity of an mTOR (mammalian target of Rapamycin) inhibitor (MTI), rapamycin, when administered with HyperCVAD (Hyperfractionated Cyclophosphamide, Vincristine, Doxorubicine and Dexamethasone), with an ultimate goal to perform a phase II study to evaluate response rates and survival in adults with Acute Lymphoblastic Leukemia (ALL) and aggressive lymphoid malignancies.

The primary objective of this trial is to characterize the feasibility, safety and tolerability of therapy with Hyper-CVAD and Rapamycin in adults with ALL and other aggressive lymphoid malignancies.

This study will evaluate the effectiveness of Rapamycin given in combination with Hyper-CVAD during A treatment cycles, and Methotrexate and Cytarabine in B treatment cycles. Both cycles will also contain the drug Rituximab if the patient has a B cell type of leukemia or lymphoma.

This combination of drugs are being studied to determine whether or not these drugs will have an effect in treating this disease.

Current therapeutic regimens for induction of remission in ALL are broadly similar. There is no single best regimen for induction therapy. The hyper-CVAD regimen is of particular interest because it does not include asparaginase as part of the therapeutic regimen and the results of induction are similar to other published regimens.

The HyperCVAD regimen with or without rituximab is also an accepted induction regimen for lymphoblastic lymphoma, Burkitt and Burkitt like lymphoma, Mantle Cell Lymphoma, and ALL in the elderly. The regimen has also been used as a salvage regimen in patients with the above diagnoses who have relapsed after another induction regimen.

This trial will add a novel agent, an mTOR inhibitor (MTI), rapamycin, to act synergistically with the HyperCVAD regimen. This is a pilot study, assessing the feasibility, safety and toxicity of this regimen, with an ultimate goal to perform a phase II study to evaluate response rates and survival.

This is a pilot study of the Hyper-CVAD regimen with Rapamycin for the treatment of adults with acute lymphoblastic leukemia or other aggressive lymphoid malignancies. The standard Hyper-CVAD regimen will be used, with the addition of the investigational agent, Rapamycin. Hyper-CVAD alone is one of the current standard induction and salvage regimens used to treat ALL and other aggressive lymphoid malignancies.

Subjects included will have either de novo, relapsed, or refractory ALL or another aggressive lymphoid malignancy.

Chemotherapy will consist of 4 'A' cycles alternating with 4 'B' cycles, every 21 days, or as count recovery allows (at least 14 days apart) as follows: 1A; 1B; 2A; 2B, 3A; 3B; 4A; 4B. This is dependent on white blood cell count recovery.

Inclusion Criteria:

1. Patients must have a diagnosis of one of the following lymphoid malignancies (new or relapsed):

   • Acute Lymphoblastic Leukemia (B and T cell, Philadelphia Chromosome Negative)
   • Burkitt Lymphoma
   • Burkitt - type Lymphoma
   • Lymphoblastic Lymphoma
   • Mantle Cell Lymphoma
   • Adult T cell Leukemia/ lymphoma

2. Patients must be >18 years old

3. Patients must have an ECOG performance status of 0 or 1(see attachment 1).

4. Patients must have a life expectancy of at least 4 weeks.

5. Patients must be able to consume oral medication.

6. Patients must have completed any radiotherapy four weeks prior to study entry, 0-2 weeks for local palliative XRT (small port).

7. Patients must have recovered from the toxic effects of any prior chemotherapy to < grade 2 (except alopecia).

8. Required initial laboratory values: Creatinine < or = 2.0mg/dL; total or direct bilirubin < or = 1.5mg/dL (if not due to the leukemia or lymphoma itself); SGPT(ALT) < or = 3xULN; glucose <200 mg/dL, negative pregnancy test for women with child-bearing potential.

9. Patients must be able to sign consent and be willing and able to comply with scheduled visits, treatment plan and laboratory testing.

10. Patients may have had a prior stem cell transplant (autologous or allogeneic), however they may not have active GvHD, nor be on any immunosuppression

Exclusion Criteria:

1. Patients must not be receiving any chemotherapy agents (except Hydroxyurea)

2. Intrathecal ARA-C and intrathecal methotrexate are permissible (as they are not systemic and only isolated to the central nervous system).

3. Patients must not be receiving growth factors, except for erythropoietin.

4. Patients with a current second malignancy requiring systemic therapy, other than non-melanoma skin cancers, are not eligible.

5. Patients with uncontrolled high blood pressure, unstable angina, symptomatic congestive heart failure, myocardial infarction within the past 6 months or serious uncontrolled cardiac arrhythmia are not eligible.

6. Patients taking any of the following drugs while on-study are not eligible:

   1. Carbamazepine (e.g. Tegretol)
   2. Rifabutin (e.g. Mycobutin)
   3. Rifampin (e.g. Rifadin)
   4. Rifapentine (e.g. Priftin)
   5. St. John's Wort- may decrease the effects of sirolimus by decreasing the amount of sirolimus in the body
   6. Clarithromycin (e.g. Biaxin)
   7. Cyclosporin e.g. (Neorla or Sandimmune)
   8. Diltiazem (e.g. Cardizem)
   9. Erythromycin (e.g. Akne-Mycin, Ery-Tab)
   10. Itraconazole (e.g. Sporanox)
   11. Ketoconazole (e.g. Nizoral)
   12. Telithromycin (e.g. Ketek)
   13. Verapamil (e.g. Calan SR, Isoptin, Verelan)
   14. Voriconazole (e.g. VFEND) - May increase the effects of sirolimus by increasing the amount of this medicine in the body. [Cannot be taken within 72 hours prior to or subsequent to receiving rapamycin, but may be taken prior to or after the above time period]
   15. Tacrolimus (e.g. Prograf) - May cause liver transplant rejection or serious side effects in patients on sirolimus.

7. Patients with known HIV positivity or AIDS-related illness are not eligible.

8. Patients with other severe concurrent disease which in the judgment of the investigator would make the patient inappropriate for entry into this study are ineligible.

9. Patients must not have evidence of cerebellar dysfunction or prior history of cerebellar dysfunction with Ara-C administration.

10. Patients must not have received any investigational agents within 30 days of study entry.

11. Patients must not be pregnant or breastfeeding. Pregnancy tests must be obtained for all females of child-bearing potential. Pregnant or lactating patients are ineligible for this study due to the unknown human fetal or teratogenic toxicities of rapamycin. Males or females of reproductive age may not participate unless they have agreed to use an effective contraceptive method.

12. Patients who have uncontrolled infection are not eligible. Patients must have any active infections under control. Fungal disease must be stable for at least 2 weeks before study entry. Patients with bacteremia must have documented negative blood cultures prior to study entry.