BV-CHEP Chemotherapy for Adult T-cell Leukemia or Lymphoma
BV-CHEP Chemotherapy for Adult T-cell Leukemia or Lymphoma
Adult T-cell leukemia/lymphoma (ATLL) is a rare form of cancer found mostly among people from
 the Caribbean islands, Western Africa, Brazil, Iran, and Japan. Most cases of this disease in
 the United States occur along the East Coast due to emigration from the Caribbean islands.
 There is currently no standard treatment for ATLL. Research shows that patients who go into
 first time remission (respond completely or partially to treatment) and have a bone marrow
 transplant have the best outcomes. Traditional chemotherapy treatments have generally not
 worked well in patients with ATLL. Additionally, not all patients will be eligible for a bone
 marrow transplant.

 The purpose of this study is to see how well individuals with ATLL respond to an
 investigational cancer treatment. This investigational treatment combines a drug called
 brentuximab vedotin with a standard chemotherapy treatment made up of cyclophosphamide,
 doxorubicin, etoposide, and prednisone. This treatment is considered investigational because
 it is not approved by the United States Food and Drug Administration (FDA) for the treatment
 of ATLL.

 Brentuximab vedotin, also known as Adcetris, is approved by the United States Food and Drug
 Administration (FDA) for treatment of certain types of lymphomas, including peripheral T-cell
 lymphomas when combined with cyclophosphamide, doxorubicin, and prednisone in patients whose
 cancer cells express a type of marker called CD30.

 Brentuximab vedotin is an antibody that also has a chemotherapy drug attached to it.
 Antibodies are proteins that are part of the immune system. They can stick to and attack
 specific targets on cancer cells. The antibody part of brentuximab vedotin sticks to a target
 called cluster of differentiation 30 (CD30) that is located on the outside of the cancer
 cells. Normal cells have little or no CD30 on their surface. ATLL cancer cells often have a
 larger amount of CD30 on their surface than normal cells. However, CD30 is found in different
 amounts on ATLL cancer cells. This study will also test the amount of CD30 found on each
 participant's cancer cells. Researchers will be looking to see if the response to the study
 treatment varies based on the amount of CD30 found on the outside participants' cancer cells.

 In another study, brentuximab vedotin was combined in another study with cyclophosphamide,
 doxorubicin, and prednisone. The study included patients with various types of T-cell
 lymphomas. Two of the patients enrolled in that study had ATLL. Both had a complete response
 (no evidence of disease). The researchers in this study (LCCC 1637) have added etoposide to
 the combination of brentuximab vedotin with cyclophosphamide, doxorubicin, and prednisone.
 They predict that the addition of etoposide will improve patient outcomes. Research shows
 that etoposide helps improve outcomes in patients with certain types of T-cell lymphomas who
 undergo chemotherapy treatment. This investigational combination of brentuximab vedotin with
 cyclophosphamide, doxorubicin, etoposide, and prednisone is called BV-CHEP.
STUDY OBJECTIVES

 Primary Objective To define the proportion of subjects with CR after 4-6 cycles of
 brentuximab vedotin in combination with cyclophosphamide, doxorubicin, etoposide, and
 prednisone (BV-CHEP) in the treatment of adult T-cell leukemia/lymphoma.

 Secondary Objectives

 To estimate the overall response rate (ORR) with 4-6 cycles of BV-CHEP therapy in patients
 with adult T-cell leukemia/lymphoma.

 To determine progression-free survival (PFS) for BV-CHEP in patients with adult T-cell
 leukemia/lymphoma who received or did not receive BV maintenance.

 To determine duration of response to BV-CHEP in patients with adult T-cell leukemia/lymphoma
 who received or did not receive BV maintenance.

 To determine overall survival (OS) of patients with adult T-cell leukemia/lymphoma treated
 with BV-CHEP who received or did not receive BV maintenance therapy.

 To evaluate the toxicity and tolerability of BV-CHEP and BV maintenance therapy via the
 National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v4.03).

 *Note: After completion or withdrawal from BV-CHEP therapy, patients will segregate into one
 of the following groups: 1) those who progressed on BV-CHEP; 2) those who completed 4-6
 cycles of BV-CHEP and went on to allogeneic transplant; 3) those who completed 6 cycles of
 BV-CHEP but were CD30 negative and ineligible for maintenance therapy; and 4) those who
 completed 6 cycles of BV-CHEP, were CD30 positive, but continued study treatment on BV in the
 maintenance phase of the study.

 ENDPOINTS

 Primary Endpoint

 Criteria for CR after 4-6 cycles of BV-CHEP will be based on the International Workshop to
 standardize response criteria for malignant lymphomas (ie, Lugano Criteria per Cheson, et al.
 J Clin Oncol. 2014;32(27):3059-68).

 Secondary Endpoints

 Criteria for overall response will be based on the International Workshop to standardize
 response criteria for malignant lymphomas (ie, Lugano Criteria per Cheson, et al. J Clin
 Oncol. 2014;32(27):3059-68).

 PFS is defined as time from D1 of treatment until disease progression (based on Lugano
 criteria) or death from any cause.

 Duration of response is defined as the time from documentation of tumor response per Lugano
 criteria to disease progression

 OS is defined as the time from D1 of treatment until death from any cause

 Toxicity and tolerability of therapy will be assessed via the NCI CTCAE v4.03

 TREATMENT INFORMATION

 Patients will undergo screening to see if they are eligible. If eligible, participants will
 start by receiving 2 cycles of BV-CHEP (cycles 1 and 2). After 2 cycles of BV-CHEP,
 participants will have a positron emission tomography/computed tomography (PET/CT) or a CT
 scan to assess their disease. If the scan shows the cancer has stayed the same or gotten
 better, participants may continue taking BV-CHEP for two more cycles (cycle 3 and 4). If, at
 any time during study treatment, a participant's disease gets worse, the participant will end
 study treatment and other treatment options will be discussed with you.

 If a participant continues on BV-CHEP, at the beginning of cycle 5, the participant will have
 a PET/CT scan. If the cancer has gotten better and the participant is eligible for a bone
 marrow transplant, he/she will have the transplant. If the participant is not eligible for a
 bone marrow transplant and the cancer has stayed the same or gotten better, the participant
 may continue on BV-CHEP for two more cycles (cycles 5 and 6).

 At the end of cycle 6 of BV-CHEP, participants will have another PET/CT scan. If the scan
 shows the cancer has gotten better and the participant is eligible for a bone marrow
 transplant, he/she will have the transplant. If a participant is not eligible for a bone
 marrow transplant and his/her cancer cells did not test positive for CD30, the participant
 will end study treatment. The study doctor will discuss other treatment options that are not
 part of this study with the participant.

 Participants may continue on brentuximab vedotin alone as maintenance therapy if:

 -  They are not eligible for a bone marrow transplant,

 -  Their cancer cells tested positive for CD30, and

 -  Their cancer has not gotten worse after taking BV-CHEP.

 Participants will be removed from BV maintenance therapy if their cancer get worse.

 DURATION OF THERAPY Therapy in LCCC 1637 involves up to 6 cycles of treatment with
 brentuximab vedotin (BV) with a chemotherapy treatment made up of cyclophosphamide,
 doxorubicin, etoposide, and prednisone (CHEP). Each cycle is 21 days long. Participants may
 continue on BV alone as maintenance therapy after 6 cycles of BV-CHEP if they meet the
 requirements outlined above. Each cycles of BV maintenance therapy is 21-day long. BV
 maintenance therapy may continue until a participant's disease progresses.

 DURATION OF FOLLOW-UP PERIOD Participants will be followed for survival for up to 5 years.
 They will also have a PET/CT or CT scan and a blood test every 6 months for 2 years after
 study treatment ends.
Inclusion Criteria:

 Subjects must meet all of the following inclusion criteria to participate in this study:

 1. Informed consent and HIPAA authorization for release of personal health information
 obtained.

 2. Age ≥ 18 years at the time of consent.

 3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.

 4. Histological confirmation of biopsy-proven peripheral T-cell leukemia/lymphoma
 consistent with ATLL

 -  Included subtypes will be: acute, lymphomatous, and chronic unfavorable. Chronic
 unfavorable is defined as the chronic variant with at least one of the following:
 lactate dehydrogenase (LDH)>upper limit of normal (ULN), blood urea nitrogen
 (BUN)>ULN, Albumin<lower limit of normal (LLN)

 -  Positive human T-lymphotropic virus-1 (HTLV-1) antibody testing with confirmatory
 testing via Western blot, enzyme-linked immunosorbent assay (ELISA), or molecular
 testing (PCR).

 5. Documented negative serologic testing for human immunodeficiency virus (HIV).

 6. If positive for HBV exposure or prior infection, can continue to participate in trial
 with prophylactic entecavir (for HBV). If positive for hepatitis c virus (HCV)
 exposure or active infection, can participate in trial with monitoring for liver
 function abnormalities.

 7. Demonstrate adequate organ function as defined below; all screening labs to be
 obtained within three days prior to study treatment.

 System: Renal -Calculated creatinine clearance

 Laboratory Value: ≥ 30 mL/min using the Cockcroft-Gault formula for subjects with
 creatinine levels > 2.0 x institutional ULN

 System: Hepatic - Bilirubin

 Laboratory Value: ≤ 3.0 mg/dL

 System: Hepatic - Aspartate aminotransferase (AST)

 Laboratory Value: ≤ 2.5 × ULN

 System: Hepatic - Alanine aminotransferase (ALT)

 Laboratory Value: ≤ 2.5 × ULN

 8. Females of childbearing potential must have a negative serum pregnancy test within
 three days (72 hours) prior to initiating study treatment. NOTE: Females are
 considered of child bearing potential unless they are surgically sterile (have
 undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they
 are naturally postmenopausal for at least 12 consecutive months.

 9. Females of childbearing potential must be willing to abstain from heterosexual
 activity or to use 2 forms of effective methods of contraception from the time of
 informed consent until 24 weeks (6 months) after treatment discontinuation. The two
 contraception methods can be comprised of two barrier methods, or a barrier method
 plus a hormonal method or an intrauterine device that meets <1% failure rate for
 protection from pregnancy in the product label.

 10. Male patients with female partners must have had a prior vasectomy or agree to use an
 adequate method of contraception (i.e., double barrier method: condom plus spermicidal
 agent) starting with the first dose of study therapy through 24 weeks (6 months) after
 the last dose of study therapy.

 11. As determined by the enrolling physician or protocol designee, willingness and ability
 of the subject to understand and comply with study procedures

 12. Prior Treatment: Previously untreated or has received a maximum of one cycle of any
 combination chemotherapy (e.g. cyclophosphamide, doxorubicin, vincristine, prednisone
 (CHOP), CHOEP, DA-EPOCH, doxorubicin, cyclophosphamide, cytarabine, vincristine,
 methotrexate/Etoposide, ifosfamide, cytarabine, methotrexate (CODOX-M/IVAC),
 HyperCVAD) within 4 weeks of signing the main consent form. Additionally, a patient
 may have taken antiretroviral therapy (e.g. azidothymidine (AZT) and/or IFN) at any
 time prior to study enrollment

 13. CD30 expression determined by flow cytometry or IHC. NOTE: If CD30 testing was
 previously done on the biopsy sample from diagnosis, this information will be
 collected. If CD30 testing was not done, an archival sample from the biopsy used for
 diagnosis will be requested and tested for CD30. CD30 testing will also be done on the
 bone marrow tissue collected from the bone marrow exam. If we are unable to obtain an
 archival sample or if the bone marrow exam is negative, a new biopsy will be performed
 to confirm the diagnosis and test for CD30.

 Exclusion Criteria:

 Subjects who meet any of the following criteria should be excluded from study
 participation:

 1. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the
 mother is being treated on study).

 2. Has a known additional malignancy that is active and/or progressive requiring
 treatment; exceptions include basal cell or squamous cell skin cancer, in situ
 cervical or bladder cancer, or other cancer for which the subject has been
 disease-free for at least five years.

 3. Previous exposure to brentuximab vedotin (BV).

 4. History of allergic response to BV-CHEP or its components or to any of the required
 prophylactic medications or reasonable alternatives.

 5. Symptomatic cardiac disease including ventricular dysfunction, left ventricular
 ejection fraction < 40%, symptomatic coronary artery disease or symptomatic
 arrhythmias

 6. Subjects with severe hepatic insufficiency Child-Pugh Score > 6

 7. Subjects with severe renal impairment (i.e., creatinine clearance ≤ 30 mL/min; see
 Appendix B - Renal Impairment Guidelines).

 8. Exclude patients with pre-existing neuropathy grade 2 or higher.

 9. Patients receiving prohibited medications listed in the patient handout provided in
 11.4 Appendix D: Prohibited Medications or Those to be used with Caution (ie,
 ketoconazole, itraconazole, ritonavir, macrolide antibiotics, erythromycin phenytoin,
 phenobarbital, carbamazepine, and valproic acid).

 10. Patients with a parenchymal brain lesion thought to be consistent with active lymphoma
 on screening CT/MRI. Of note, patients with cerebrospinal fluid (CSF) involvement
 alone are not excluded.