Upon enrollment, patients will undergo a comprehensive history and physical exam, along with
baseline laboratory assessment. Baseline CT imaging will be required within 4 weeks prior to
study entry. Archival tissue is mandatory; a fresh biopsy of the primary tumor or a
metastatic lesion prior to initiation of therapy is optional and post-treatment tumor biopsy
is strongly encouraged.
In the phase Ib portion, eligible patients will receive APG-1252 at the assigned dose-level
on days 1, 8 and 15 plus a fixed-dose of paclitaxel 80 mg/m˄2 on days 1 and 8 of a 21-day
cycle. There will be three dose-levels of APG-1252 (-1, 80 mg; 1, 160 mg; 2, 240 mg) with the
first patient starting at dose-level 1 and subsequent patients at dose-levels determined by
the TITE-CRM methodology. There will be no intra-patient dose-escalation. Patients will be
continuously assessed for adverse events, including DLTs which are defined in the protocol.
Response assessment by CT imaging will occur every 2 cycles and treatment will continue until
progression of disease, unacceptable toxicity, patient preference to stop treatment,
withdrawal of consent, or administrative discontinuation.
In the phase II portion, eligible patients will receive APG-1252 at the RP2D determined in
the phase Ib portion on days 1, 8 and 15 plus paclitaxel 80 mg/m˄2 on days 1 and 8 of a
21-day cycle. Response assessment by CT imaging will occur every 2 cycles and treatment will
continue until progression of disease, unacceptable toxicity, patient preference to stop
treatment, withdrawal of consent, or administrative discontinuation.
Inclusion Criteria:
- Histologically or cytologically confirmed SCLC
- Progression of disease on or after initial treatment with platinum-based therapy with
or without thoracic radiotherapy; patients may have also received prior immunotherapy
or other chemotherapy agents, except for paclitaxel; there is no limit on the number
of prior treatment regimens allowed
- Male or non-pregnant, non-lactating female patients
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1
- Adequate hematologic function as indicated by:
1. Platelet count ≥ 100,000/mm˄3 Note: Use of transfusions or thrombopoietic agents
to achieve baseline platelet count criterion is prohibited.
2. Hemoglobin ≥ 9.0 g/dL
3. Absolute neutrophil count (ANC) ≥ 1000/µL Note: Use of growth-factors to maintain
ANC criterion prior to enrollment is not permitted.
- Adequate renal and liver function as indicated by:
1. Serum creatinine ≤ 1.5 × upper limit of normal (ULN); if serum creatinine is >
1.5 × ULN, creatinine clearance must be ≥ 50 mL/min
2. Total bilirubin ≤ 1.5 × ULN; If patient has Gilbert's syndrome, may have
bilirubin > 1.5 × ULN
3. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × ULN;
for patients with known liver metastases, AST and ALT may be ≤ 5 × ULN
4. Coagulation: activated partial thromboplastin time (aPTT) and prothrombin time
(PT) ≤ 1.2 × ULN
- Patients with previously treated, clinically controlled brain metastases are allowed.
Clinically controlled is defined as surgical excision and/or radiation therapy
followed by at least 14 days of stable neurologic function and no evidence of central
nervous system (CNS) disease progression as determined by CT or MRI within 14 days
prior to study enrollment. Continued use of corticosteroids is permissible.
- Willingness to use contraception by a method that is deemed effective by the
investigator by both males and female patients of child bearing potential and their
partners throughout the treatment period and for at least three months following the
last dose of study drug (postmenopausal women must have been amenorrheic for at least
12 months to be considered of non-childbearing potential).
- Able to understand and willing to sign a written informed consent form
- Able and willing to comply with study procedures and follow-up examination
Exclusion Criteria:
- Receiving concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery,
immunotherapy, hormonal therapy, targeted therapy, biologic therapy) or any
investigational therapy within 14 days prior to the first dose of treatment, with the
exception of hormones for hypothyroidism, estrogen replacement therapy (ERT),
anti-estrogen analogs, or agonists required to suppress serum testosterone levels
- Continuance of toxicities due to prior treatment that do not recover to < grade 2,
except for clinically insignificant toxicities such as lymphopenia or alopecia
- Known bleeding diathesis/disorder
- Recent history of non-chemotherapy induced thrombocytopenia associated a major
bleeding episode within 1 year prior to study entry
- Active immune thrombocytopenic purpura (ITP), active autoimmune hemolytic anemia
(AIHA), or a history of being refractory to platelet transfusions, within 1 year prior
to the first dose of study drug
- Serious gastrointestinal bleeding within 3 months of study entry
- Use of therapeutic doses of anti-coagulants is an exclusion, including anti-platelet
agents. Use of low-dose anticoagulation medications to maintain the patency of a
central intravenous catheter or aspirin (<100 mg) for cardiovascular protection are
permitted.
- Failure to recover adequately from prior surgical procedures, as judged by the
investigator. Patients who have had major surgery within 28 days from study entry, and
patients who have had minor surgery within 14 days of study entry are excluded. (Minor
surgery is invasive operative procedure involving resecting skin or mucus membranes
and connective tissue. Major surgery is an invasive operative procedure involving more
extensive resection, such as body cavity opening or organ resection.)
- Unstable angina, myocardial infarction, or a coronary revascularization procedure
within 180 days of study entry
- Active symptomatic fungal, bacterial and/or viral infection including, but not limited
to, active human immunodeficiency virus (HIV) or viral hepatitis (B or C); testing for
hepatitis B and C is not required for study enrollment
- Uncontrolled concurrent illness that would limit compliance with the study
requirements, including, but not limited to: serious uncontrolled infection,
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or
psychiatric illness
- Prior treatment with a Bcl-2/Bcl-xL inhibitor
- Prior treatment with paclitaxel
