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A Phase 1 Study of R-(-)-Gossypol (AT-101) in Combination With Cisplatin and Etoposide in Patients With Advanced Solid Tumors and Extensive-Stage Small Cell Lung Cancer


Phase 1
18 Years
N/A
Not Enrolling
Both
Extensive Stage Small Cell Lung Cancer, Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

A Phase 1 Study of R-(-)-Gossypol (AT-101) in Combination With Cisplatin and Etoposide in Patients With Advanced Solid Tumors and Extensive-Stage Small Cell Lung Cancer


PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) or recommended phase II dose (RP2D) of
AT-101 (R-(-)-gossypol) when combined with cisplatin and etoposide in patients with
advanced, refractory solid tumors and/or extensive stage small cell lung cancer (ES-SCLC).
In addition, to determine the MTD or RP2D of AT-101 when combined with cisplatin, etoposide,
and Neulasta.

II. To evaluate the toxicity and tolerability of AT-101 in combination with cisplatin and
etoposide in patients with advanced, refractory solid tumors and/or ES-SCLC. In addition,
evaluate the toxicity and tolerability of AT-101 with cisplatin, etoposide, and Neulasta.

III. To evaluate the antitumor activity of this combination per tumor measurements using the
Response Evaluation Criteria In Solid Tumors (RECIST) criteria.

SECONDARY OBJECTIVES:

I. To evaluate the pharmacokinetics of AT-101 as a single agent and in combination with
cisplatin and etoposide in plasma.

II. To perform pharmacodynamic studies (genotyping of drug metabolizing enzymes, gene
expression, and proteomics of drug-related pathways) on archived blood samples from patients
treated with AT-101 in combination with cisplatin and etoposide.

OUTLINE: This is a dose-escalation study of R-(-)-gossypol.

Patients receive oral R-(-)-gossypol twice daily on days 1-3, cisplatin intravenously (IV)
over 60 minutes on day 1*, and etoposide IV over 30 minutes on days 1*-3. Treatment repeats
every 21 days for up to 6 courses during the dose escalation and 4 courses in the expanded
extensive stage small cell lung cancer cohort, in the absence of disease progression or
unacceptable toxicity.

Blood samples are collected on day 1 of courses 1 and 2 for pharmacokinetic analysis,
biomarker assays, and correlative studies.

After completion of study treatment, patients are followed for 30 days.

[Note: *Cisplatin and etoposide will be started on day 2 during course 1; they will be given
on day 1 during all subsequent courses.]


Inclusion Criteria:



- In the dose-escalation cohorts: patients must have histologically confirmed
malignancy that is metastatic or unresectable and for which standard curative or
palliative measures do not exist or are no longer effective; in the MTD expansion
cohort: patients must have histologically or cytologically confirmed extensive-stage
small cell lung cancer

- Patients must not have received prior therapy that inhibits the B-cell lymphoma 2
(Bcl-2) family

- Patients with small cell lung cancer may have received prior prophylactic cranial
irradiation

- Prior whole brain radiotherapy allowed for patients with brain metastases provided
they have stable/improved lesions for at least 1 month following treatment, no
neurological symptoms and not require corticosteroids; an magnetic resonance imaging
(MRI) of the brain or computed tomography (CT) scan of the head must be performed at
baseline if patient has a history of brain metastases

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- Life expectancy of greater than 12 weeks

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Total bilirubin < 1.5 mg/dL

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT])
=< 2.5 x institutional upper limit of normal

- Serum creatinine < 1.5 x institutional upper limit of normal OR

- Creatinine clearance >= 45 mL/min/1.73 m^2, as calculated by Cockroft-Gault formula,
for patients with creatinine levels above institutional normal; a 24 hour urine
collection and creatinine clearance can be measured if indicated

- 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; abstinence) 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 should display the ability to understand and the willingness to sign a
written informed consent document

- Female patients of child bearing potential must not be pregnant

- Patients must have measurable or evaluable disease

Exclusion Criteria:

- Patients without small cell lung cancer who have had chemotherapy, radiotherapy or
hormonal therapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to
entering the study or those who have not recovered (=< grade 1) from clinically
significant adverse events due to agents administered more than 4 weeks earlier;
prior treatment with a platinum-based chemotherapy regimen in combination with
thoracic radiation therapy is allowed for patients with ES-SCLC provided that
recurrence of the SCLC occurred more than 6 months from definitive therapy for
limited-stage small cell lung cancer; no other prior chemotherapy is allowed for the
patients with ES-SCLC

- Failure to recover fully (as judged by the investigator) from prior surgical
procedures

- 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; if patient requires
routine use of erythropoietin, eligibility at investigator discretion

- 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 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 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

- Human immunodeficiency virus (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 (based on investigator discretion)

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Toxicity and tolerability of R-(-)-gossypol acetic acid in combination with cisplatin and etoposide in terms of types and severities by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0

Outcome Description:

The 95% confidence interval will be obtained.

Outcome Time Frame:

Assessed up to 30 days after completion of study treatment

Safety Issue:

Yes

Principal Investigator

Anne Traynor

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Wisconsin Hospital and Clinics

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2009-00273

NCT ID:

NCT00544596

Start Date:

September 2007

Completion Date:

Related Keywords:

  • Extensive Stage Small Cell Lung Cancer
  • Unspecified Adult Solid Tumor, Protocol Specific
  • Lung Neoplasms
  • Small Cell Lung Carcinoma
  • Neoplasms

Name

Location

University of Wisconsin Hospital and ClinicsMadison, Wisconsin  53792-0001
Sanford Cancer Center-Oncology ClinicSioux Falls, South Dakota  57104
UW Health Oncology - 1 South ParkMadison, Wisconsin  53715
Gundersen LutheranLa Crosse, Wisconsin  54601