INCLUSION CRITERIA:
PHASE 1A AND PHASE 1B INCLUSION CRITERIA
A subject will be eligible for study participation if he/she meets the following criteria:
1. Subject must be greater than or equal to 18 years of age.
2. Subject must have histologically documented diagnosis of a lymphoid malignancy as defined in the World Health Organization (WHO) classification scheme, except as noted in Exclusion Criteria.
3. Subject has received at least 1 prior chemotherapy treatment regimen for a lymphoid malignancy and their disease is refractory or the subject has experienced progressive disease following the treatment.
4. If clinically indicated (e.g., subjects over the age of 70) subjects must have documented brain imaging (MRI or CT) negative for subdural or epidural hematoma within 28 days prior to the first dose of study drug.
5. Subject has an Eastern Cooperative Oncology Group (ECOG) performance score of less than or equal to 1.
6. Subjects receiving Selective Serotonin Reuptake Inhibitor (SSRI) anti-depressants (e.g., Prozac) must be receiving a stable dose for at least 21 days prior to the first dose of study drug.
7. Subject must have adequate bone marrow, renal and hepatic function, independent of growth factor support (with the exception of subjects with bone marrow heavily infiltrated with underlying disease [80% or more], per local laboratory reference range as follows:
-Bone marrow: Absolute Neutrophil count (ANC) greater than or equal to 1,000/microliters; platelets greater than or equal to 100,000/mm(3); Hemoglobin greater than or equal to 9.0 g/dL;
-Renal function: serum creatinine less than or equal to 2.0 mg/dL or calculated creatinine clearance greater than or equal to 50;
-Hepatic function and enzymes: AST and ALT less than or equal to 3.0 times the upper normal limit (ULN) of institution's normal range; Bilirubin less than or equal to 1.5 times ULN. Subjects with Gilbert's Syndrome may have a Bilirubin greater than 1.5 times ULN;
-Coagulation: aPTT, PT not to exceed 1.2 times ULN.
8. Female subjects must be surgically sterile, postmenopausal (for at least one year), or have negative results for a pregnancy test performed as follows:
-At Screening on a serum sample obtained within 14 days prior to initial study drug administration, and
-Prior to dosing on a urine sample obtained on Cycle 1 Day -3 (Phase 1a) or Lead-in Day 7 (Phase 1b) if it has been greater than 7 days since obtaining the serum pregnancy test results.
9. Female subjects not surgically sterile or postmenopausal (for at least one year) and non-vasectomized male subjects must practice at least one of the following methods of birth control:
-total abstinence from sexual intercourse (minimum one complete menstrual cycle);
-a vasectomized partner;
-hormonal contraceptives (oral, parenteral or transdermal) for at least three months prior to study drug administration;
-double-barrier method (including condoms, contraceptive sponge, diaphragm or vaginal ring with spermicidal jellies or cream).
10. Subject must voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study-specific procedures.
EXCLUSION CRITERIA:
PHASE 1A AND PHASE 1B EXCLUSION CRITERIA:
A subject will not be eligible for study participation if he/she meets any of the following criteria:
1. Subject has been diagnosed with Post-Transplant Lymphoproliferative Disease (PTLD), Burkitt's lymphoma, Burkitt-like lymphoma, lymphoblastic lymphoma/leukemia, multiple myeloma, or HIV-associated lymphoma.
2. Subject has a history of or is clinically suspicious for cancer-related Central Nervous System (CNS) disease, lymphoid or non-lymphoid.
3. Subject has undergone an allogeneic or autologous stem cell transplant.
4. Subject has an underlying, predisposing condition of bleeding or currently exhibits signs of bleeding. The subject has a recent history of non-chemotherapy induced thrombocytopenic associated bleeding within one year prior to the first dose of study drug.
5. Subject has active peptic ulcer disease or other hemorrhagic esophagitis/gastritis.
6. The subject has active immune thrombocytopenic purpura or a history of being refractory to platelet transfusions (within 1 year prior to the first dose of study drug).
7. Subject has a significant history of cardiovascular disease (e.g., MI, thrombotic or thromboembolic event in the last 6 months), renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, or hepatic disease that in the opinion of the investigator would adversely affect his/her participating in this study. Questions regarding inclusion of individual subjects should be directed to the Abbott Medical Monitor or designee.
8. Female subject is pregnant or breast-feeding.
9. Subject has tested positive for HIV (due to potential drug-drug interactions between anti-retroviral medications and ABT-263, as well as anticipated ABT-263 mechanism based lymphopenia that may potentially increase the risk of opportunistic infections and potential drug-drug interactions with certain anti-infective agents).
10. Subject has previous or current malignancies at other sites, with the exception of:
-adequately treated in situ carcinoma of the cervix uteri;
-basal or squamous cell carcinoma of the skin;
-previous malignancy (e.g., localized prostate cancer) confined and surgically resected with no evidence of disease within three years.
11. Subject exhibits evidence of other clinically significant uncontrolled condition(s) including, but not limited to:
-active systemic fungal infection;
-diagnosis of fever and neutropenia within one week prior to study drug administration.
12. Subject has received steroid therapy within seven days prior to the first dose of study drug for anti-neoplastic intent.
13. The subject has received any anti-cancer therapy including chemotherapy, immunotherapy, radiotherapy, hormonal (with the exception of hormones for hypothyroidism or estrogen replacement therapy [ERT]), or any investigational therapy within 14 days prior to the first dose of study drug, or has not recovered to less than grade 2 clinically significant adverse effect(s)/toxicity(s) of the previous therapy.
14. The subject has received a biologic within 30 days prior to the first dose of study drug.
15. Subject is currently receiving or requires anticoagulation therapy or any drugs or herbal supplements that effect platelet function, with the exception of low-dose anticoagulation medications that are used to maintain the patency of a central venous catheter.
16. Subject has received aspirin within seven days prior to the first dose of study drug and during ABT-263 administration.
17. Subject has consumed grapefruit or grapefruit products within 3 days prior to the first dose of study drug.
PHASE 2A INCLUSION CRITERIA:
A subject will be eligible for study participation if he/she meets the following criteria:
1. Subject must be greater than or equal to 18 years of age.
2. Subjects enrolling in:
-Arm A must have a histologically documented diagnosis of follicular lymphoma.
-Arm B must have a histologically documented diagnosis of mantle cell lymphoma, peripheral T-cell lymphoma, cutaneous T-cell lymphoma including mycosis fungoides and Sezary syndrome and other indolent B-cell lymphomas such as marginal zone lymphoma.
-Arm C must have a histologically documented diagnosis of diffuse large B-cell lymphoma.
3. Subject must have measurable disease by International Working Group (IWG) Criteria for Tumor Response.
4. Subject must have relapsed or refractory disease and require treatment in the opinion of the investigator.
5. If clinically indicated (e.g., subjects over the age of 70) subjects must have documented brain imaging (MRI or CT) negative for subdural or epidural hematoma within 28 days prior to the first dose of study drug.
6. Subject must have archived diagnostic tissue available for assessment of Bcl-2 family protein expression.
7. Subject has one of the following available for pharmacodynamic analyses:
-Core needle biopsy of malignant lymph node obtained at Screening;
-Bone marrow aspirate or core obtained at Screening, positive for lymphoma;
-Archived tumor tissue with no intervening treatment since the biopsy (e.g., from debulking, tissue obtained at relapse or bone marrow sample).
8. Subject has an Eastern Cooperative Oncology Group performance score of less than or equal to 1.
9. Subjects receiving Selective Serotonin Reuptake Inhibitor (SSRI) anti-depressants (e.g., Prozac) must be receiving a stable dose for at least 21 days prior to the first dose of study drug.
10. Subject must have adequate bone marrow, renal and hepatic function, independent of growth factor support (with the exception of subjects with bone marrow that is heavily infiltrated with underlying disease [80% or more]), per local laboratory reference range as follows:
-Bone marrow: Absolute Neutrophil count (ANC) greater than or equal to 1,000/microliters;
Platelets greater than or equal to 100,000/mm3; Hemoglobin greater than or equal to 9.0 g/dL;
-Renal function: Serum creatinine less than or equal to 2.0 mg/dL or calculated creatinine clearance greater than or equal to 50;
-Hepatic function and enzymes: AST and ALT less than or equal to 3.0 times the upper normal limit (ULN) of institution's normal range; Bilirubin less than or equal to 1.5 times ULN. Subjects with Gilbert's Syndrome may have a Bilirubin greater than 1.5 times ULN;
-Coagulation: aPTT, PT not to exceed 1.2 times ULN.
11. Subjects who have a history of an autologous bone marrow transplant must be greater than 6 months post transplant and have adequate bone marrow independent of any growth stimulating factors (with the exception of subjects with bone marrow that is heavily infiltrated with underlying disease [80% or more]), renal and hepatic function per local laboratory reference range as follows:
-Bone marrow: Absolute Neutrophil count (ANC) greater than or equal to 1500/mL; Platelets greater than or equal to 125,000/mm3; Hemoglobin greater than or equal to 10.0 g/dL;
-Renal function: serum creatinine less than or equal to 2.0 mg/dL or calculated creatinine clearance greater than or equal to 50;
-Hepatic function and enzymes: AST and ALT less than or equal to 3.0 times the upper normal limit (ULN) of institution's normal range; Bilirubin less than or equal to 1.5 times ULN. Subjects with Gilbert's Syndrome may have a Bilirubin greater than 1.5 times ULN;
-Coagulation: aPTT, PT not to exceed 1.2 times ULN.
12. Female subjects must be surgically sterile, postmenopausal (for at least one year), or have negative results for a pregnancy test performed as follows:
-At Screening on a serum sample obtained within 14 days prior to initial study drug administration, and
-Prior to dosing on a urine sample obtained on Cycle 1 Day if it has been greater than 7 days since obtaining the serum pregnancy test results 1.
13. Female subjects not surgically sterile or postmenopausal (for at least one year) and non-vasectomized male subjects must practice at least one of the following methods of birth control:
-total abstinence from sexual intercourse (minimum one complete menstrual cycle);
-a vasectomized partner;
-hormonal contraceptives (oral, parenteral or transdermal) for at least three months prior to study drug administration;
-double-barrier method (including condoms, contraceptive sponge, diaphragm or vaginal ring with spermicidal jellies or cream).
14. Subject must voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study-specific procedures.
PHASE 2A EXCLUSION CRITERIA
A subject will not be eligible for study participation if he/she meets any of the following criteria:
1. Subject has a history of or is clinically suspicious for cancer-related CNS disease, lymphoid or non-lymphoid.
2. Subject has undergone an allogeneic stem cell transplant.
3. Subject has an underlying, predisposing condition of bleeding or currently exhibits signs of bleeding. The subject has a recent history of non-chemotherapy induced thrombocytopenic associated bleeding within one year prior to first dose of study drug.
4. Subject has active peptic ulcer disease or other hemorrhagic esophagitis/gastritis.
5. The subject has active immune thrombocytopenic purpura or a history of being refractory to platelet transfusions (within 1 year prior to the first dose of study drug).
6. Subject has a significant history of cardiovascular disease (e.g. MI, thrombotic or thromboembolic event in the last 6 months), renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, or hepatic disease that in the opinion of the investigator would adversely affect his/her participating in this study. Questions regarding inclusion of individual subjects should be directed to the Abbott Medical Monitor or designee.
7. Female subject is pregnant or breast-feeding.
8. Subject has tested positive for HIV (due to potential drug-drug interactions between anti-retroviral medications and ABT-263, as well as anticipated ABT-263 mechanism based lymphopenia that may potentially increase the risk of opportunistic infections and potential drug-drug interactions with certain anti-infective agents).
9. Subject has previous or current malignancies at other sites, with the exception of:
-adequately treated in situ carcinoma of the cervix uteri;
-basal or squamous cell carcinoma of the skin;
-previous malignancy (e.g., localized prostate cancer) confined and surgically resected with no evidence of disease within three years.
10. Subject exhibits evidence of other clinically significant uncontrolled condition(s) including, but not limited to:
-active systemic fungal infection;
-diagnosis of fever and neutropenia within 1 week prior to study drug administration.
11. Subject has received steroid therapy within seven days prior to the first dose of study drug for anti-neoplastic intent.
12. The subject has received any anti-cancer therapy including chemotherapy, immunotherapy, radiotherapy, hormonal (with the exception of hormones for hypothyroidism or estrogen replacement therapy [ERT]), or any investigational therapy within 14 days prior to the first dose of study drug, or has not recovered to less than grade 2 clinically significant adverse effect(s)/toxicity(s) of the previous therapy.
13. The subject has received a biologic within 30 days prior to the first dose of study drug.
14. Subject has received aspirin within seven days prior to the first dose of study drug and during ABT-263 administration.
15. Subject is currently receiving or requires anticoagulation therapy or any drugs or herbal supplements that effect platelet function, with the exception of low-dose anticoagulation medications that are used to maintain the patency of a central venous catheter.
16. Subject has consumed grapefruit or grapefruit products within 3 days prior to the first dose of study drug.
National Institutes of Health Clinical Center
Bethesda, Maryland 20892. Last update: 09/20/2008