Investigation of Tipifarnib in Treatment of Subjects With Peripheral T-Cell Lymphoma (PTCL) That Have Not Responded to Standard Therapy

An Open Label Phase II Study of Tipifarnib in Subjects With Relapsed or Refractory Peripheral T-Cell Lymphoma

Phase II study designed to investigate antitumor activity in terms of objective response rate (ORR) of tipifarnib subjects with advanced Peripheral T-Cell Lymphoma (PTCL). Tipifarnib will be administered orally until disease progression.

This Phase II study will investigate the antitumor activity in terms of ORR of tipifarnib in subjects with relapsed or refractory PTCL. The first 18 subjects may be of the following PTCL sub-types: PTCL not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), ALK-positive and negative anaplastic large cell lymphoma (ALCL), hepatosplenic T-cell lymphoma, enteropathy-associate T-cell lymphoma (EATL), extranodal natural killer (NK) T-cell lymphoma, nasal type and subcutaneous panniculitis-like T-cell lymphoma. The AITL expansion cohort (N=32) will enroll only subjects with AITL. An additional cohort of patients (N=12) expressing the wild type CXCL12 3' UTR will be enrolled in order to explore the benefits of tipifarnib treatment observed in patients having an absence of this gene variation or single nucleotide variation (SNV).

Tumor response assessments will be conducted according to Lugano Classification and/or mSWAT criteria.

Tumor assessments will be performed approximately every 8 weeks (cycles 2-6) and at least once approximately every 12 weeks thereafter (Cycles 9, 12, 15, etc.), and will continue until disease progression. Subjects experiencing a complete response may be considered for bone marrow transplantation. Upon disease progression, all subjects will be followed for survival and the use of subsequent therapy. All subjects will be followed for safety during treatment and up to approximately 30 days after treatment discontinuation or until before the initiation of another anti-cancer therapy. Additional follow up may be implemented until the subject recovers from any emergent treatment related toxicity or the adverse event is considered irreversible by the investigator.

Inclusion Criteria:

1. Diagnosis of PTCL according to the most recent edition of the World Health Organization (WHO) Classification of Tumors of Hematopoietic or Lymphoid Tissues, as follows:

   1. Anaplastic large cell lymphoma (ALCL), ALK positive
   2. ALCL, ALK negative
   3. Angioimmunoblastic T-cell lymphoma (AITL)
   4. Enteropathy-associated T-cell lymphoma
   5. Extranodal natural killer (NK) T-cell lymphoma, nasal type
   6. Hepatosplenic T-cell lymphoma
   7. Peripheral T-cell lymphoma, not otherwise specified (NOS)
   8. Subcutaneous panniculitis-like T-cell lymphoma

2. For enrollment into the AITL expansion cohort, subjects must have the diagnosis of AITL, nodal PTCL with T-follicular helper phenotype or follicular PTC.

3. For enrollment into the CXCL12+ PTCL expansion cohort, subjects must have the diagnosis of PTCL (a - h subtypes listed above, except AITL), consent to provide buccal swabs for CXCL12 SNP testing, and be found to be CXCL12+ based on testing by a Sponsor approved methodology.

4. Relapsed or are refractory to at least 1 prior systemic cytotoxic therapy. -Subjects must have received conventional therapy as a prior therapy.

5. Subject has consented to provide at least 6 unstained tumor slides (10 preferred) or an FFPE block for biomarker testing.

6. Subject has measurable disease as determined by the Lugano Classification and/or mSWAT.

7. At least 2 weeks since the last systemic therapy regimen prior to enrollment.

8. At least 2 weeks since last radiotherapy if radiation was localized to the only site of measurable disease, unless there is documentation of disease progression of the irradiated site. Subjects must have recovered from all acute toxicities from radiotherapy.

9. ECOG performance status of 0-2

10. Acceptable liver and renal function

11. Acceptable hematologic status

12. Female subjects must be either:

    1. Of non-child-bearing potential (surgically sterilized or at least 2 years post- menopausal); or
    2. If of child-bearing potential, subject must use an adequate method of contraception consisting of two-barrier method or one barrier method with a spermicide or intrauterine device. Both females and male subjects with female partners of child- bearing potential must agree to use an adequate method of contraception for 2 weeks prior to screening, during, and at least 4 weeks after last dose of trial medication. Female subjects must have a negative serum or urine pregnancy test within 72 hours prior to start of trial medication.
    3. Not breast feeding at any time during the study.

13. Written and voluntary informed consent.

Exclusion Criteria:

1. Diagnosis of any of the following:

   1. Precursor T-cell lymphoma or leukemia
   2. Adult T-cell lymphoma/leukemia (ATLL)
   3. T-cell prolymphocytic leukemia
   4. T-cell large granular lymphocytic leukemia
   5. Primary cutaneous type anaplastic large cell lymphoma
   6. Mycosis fungoide/Sezary syndrome

2. Ongoing treatment with an anticancer agent not contemplated in this protocol.

3. Prior treatment (at least 1 full treatment cycle) with an FTase inhibitor.

4. Any history of clinically relevant coronary artery disease or myocardial infarction within the last 3 years.

5. Known central nervous system lymphoma.

6. Stem cell transplant less than 3 months prior to enrolment.

7. Non-tolerable > Grade 2 neuropathy or evidence of unstable neurological symptoms within 4 weeks of Cycle 1 Day 1.

8. Major surgery, other than diagnostic surgery, within 2 weeks prior to Cycle 1 Day 1, without complete recovery.

9. Other active malignancy requiring therapy such as radiation, chemotherapy, or immunotherapy.

10. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy.

    Known infection with HIV, or an active infection with hepatitis B or hepatitis C.

11. Subjects who have exhibited allergic reactions to tipifarnib, or structural compounds similar to tipifarnib or to its excipients. This includes hypersensitivity to imidazoles, such as clotrimazole, ketoconazole, miconazole and others in this drug class.

12. Concomitant disease or condition that could interfere with the conduct of the study, or that would, in the opinion of the investigator, pose an unacceptable risk to the subject in this study.

13. The subject has legal incapacity or limited legal capacity.

14. Dementia or significantly altered mental status that would limit the understanding or rendering of informed consent and compliance with the requirements of this protocol.

15. Unwillingness or inability to comply with the study protocol for any reason.