A Phase 1 Study of R-(-)-Gossypol (Ascenta's AT-101) in Combination With Paclitaxel and Carboplatin in Solid Tumors

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed malignancy that is
metastatic and unresectable and for which standard curative or palliative measures do
not exist or are no longer effective; patient may have previously treated or
untreated disease

- Patients may have had no more than nine months of previous marrow damaging cytotoxic
chemotherapy; examples include but are not limited to: platinum agents
cyclophosphamide, ifosfamide, BCNU, and mitomycin C; chemotherapy agents that are
non-alkylators such as fluorouracil or taxanes will not be considered marrow damaging
chemotherapy; patients must be at least 28 days from last prior chemotherapy or
molecular therapy; at least six weeks from last chemotherapy if the regimen included
BCNU or mitomycin C; it must be at least 2 weeks from last radiation therapy and less
than a total of 30% of the bone marrow receiving radiation dose > 3000 cGy; in
addition, patients may not have received previous high-dose therapy requiring
hematopoietic stem cell transplantation nor can they have received anti-cancer
treatments involving radioactive pharmaceuticals

- Patients with non-Hodgkins lymphoma that is amenable to hematopoietic stem cell
transplantation with curative intent may participate only if stem cell transplant is
refused or is not indicated

- ECOG performance status =< 2, Karnofsky ≥ 60%

- Life expectancy of greater than 3 months

- Absolute Neutrophil Count ≥ 1,500/uL

- Platelets ≥ 100,000/uL

- Total bilirubin within normal institutional limits

- AST (SGOT)/ALT (SGPT) =< 2.5 X institutional ULN

- Creatinine within normal institutional limits OR a measured creatinine clearance by
24 hour urine collection greater than 60 mL/min; a calculated creatinine clearance by
Cockcroft-Gault Formula is acceptable in lieu of a measured value

- All Patients must have Measurable or Evaluable Disease per RECIST Criteria

- The effects of AT-101 on the developing human fetus are unknown; for this reason and
because other therapeutic agents used in this trial are known to be teratogenic,
women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control) prior to study entry, for the duration
of study participation, and for at least one month following the last dose of AT-101;
should a woman become pregnant or suspect she is pregnant while participating in this
study, she should inform her treating physician immediately

- Patients with previously treated brain metastases who are clinically and
radiographically stable or improved at least four weeks after completion of radiation
therapy and are off steroids are eligible; an MRI of the brain or CT scan of the head
with contrast must be performed at baseline for patients with history of and/or
symptoms suspicious of brain metastases

- Patients must sign informed consent

Exclusion Criteria:

- Treatment with chemotherapy, hormonal agents (except LHRH agonists/antagonists) used
for their anti-cancer activity, or biologic response modifiers within 4 weeks (6
weeks for nitrosoureas or mitomycin C) prior to entering the study

- Failure to recover fully (as judged by the investigator) from prior surgical
procedures, or failure to recover from adverse events due to agents administered more
than 4 weeks earlier

- Concurrent treatment with an investigational agent other than the investigational
agent(s) used in this study OR treatment within 4 weeks of study entry with any
investigational agent(s) or device(s)

- Any prior use of racemic gossypol or AT-101

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to AT-101 or other agents used in study

- Requirement for routine use of hematopoietic growth factors (including granulocyte
colony stimulating factor, granulocyte macrophage colony stimulating factor, or
interleukin-11) or platelet transfusions to maintain absolute neutrophil counts or
platelets counts above the required thresholds for study entry; use of erythropoietin
stimulating agents and RBCs prior to study enrollment is allowed

- Neuropathy is a well described side effect of paclitaxel and carboplatin; patients
may not have baseline peripheral neuropathy >= Grade 2

- Any condition (e.g., gastrointestinal tract disease resulting in an inability to take
oral medication or a requirement for IV alimentation, prior surgical procedures
affecting absorption, or active peptic ulcer disease) that impairs their ability to
swallow and retain AT-101 tablets

- Patients with malabsorption syndrome, disease significantly affecting
gastrointestinal function, or resection of the stomach or small bowel within the last
three months are excluded; subjects with ulcerative colitis, inflammatory bowel
disease, or a partial or complete small bowel obstruction are also excluded

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would affect safety or
limit compliance with study requirements

- Pregnant women are excluded from this study because the effects of AT-101 on the
developing human fetus are unknown, but could potentially include teratogenic or
abortifacient effects; because there is an unknown but potential risk for adverse
events in nursing infants secondary to treatment of the mother with AT-101,
breastfeeding should be discontinued if the mother is treated with AT-101; these
potential risks may also apply to other agents used in this study

- HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with AT-101 or other agents used in
this study; in addition, these patients are at increased risk of lethal infections
when treated with marrow-suppressive therapy; appropriate studies will be undertaken
in patients receiving combination antiretroviral therapy when indicated

- Patients with > grade 2 symptomatic hypercalcemia

- Patients with a myocardial infarction (MI) or cardiac (heart) surgery within the past
3 months