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Phase I Study of Dasatinib in Combination With Ipilimumab for Patients With Advanced Gastrointestinal Stromal Tumor and Other Sarcomas


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Chondrosarcoma, Clear Cell Sarcoma of the Kidney, Endometrial Stromal Sarcoma, Ewing Sarcoma of Bone, Extraosseous Ewing Sarcoma, Gastrointestinal Stromal Tumor, Mast Cell Sarcoma, Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor, Metastatic Osteosarcoma, Ovarian Sarcoma, Recurrent Adult Soft Tissue Sarcoma, Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor, Recurrent Osteosarcoma, Recurrent Uterine Sarcoma, Stage III Adult Soft Tissue Sarcoma, Stage III Uterine Sarcoma, Stage IV Adult Soft Tissue Sarcoma, Stage IV Uterine Sarcoma

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Trial Information

Phase I Study of Dasatinib in Combination With Ipilimumab for Patients With Advanced Gastrointestinal Stromal Tumor and Other Sarcomas


PRIMARY OBJECTIVES:

I. To assess the safety and tolerability of treatment with ipilimumab in combination with
dasatinib in subjects with gastrointestinal stromal tumor (GIST) and other advanced
sarcomas.

SECONDARY OBJECTIVES:

I. Response rate (RR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1,
immune-related response criteria, and Choi criteria.

II. Progression free survival (PFS). III. Progression-free survival at 6 months
(PFS6months). IV. Overall survival (OS). V. Immunological correlative studies.

OUTLINE: This is a dose-escalation study.

Patients receive dasatinib orally (PO) once daily (QD) for 7 days. Patients then receive
dasatinib PO QD and ipilimumab intravenously (IV) once on weeks 1, 4, 7 and 10. Beginning on
week 24, patients then receive dasatinib PO QD and ipilimumab IV once every 12 weeks.
Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 4 weeks and then every 3
months.


Inclusion Criteria:



- DOSE ESCALATION COHORT:

- Subjects must have histologically or cytologically confirmed sarcoma that is
metastatic or unresectable

- Patients must have had at least one prior therapy

- DOSE EXPANSION COHORT:

- Subjects must have histologically or cytologically confirmed GIST that is metastatic
or unresectable

- GIST patients must have had progression on or have been intolerant to imatinib and
sunitinib

- Subjects enrolled in the maximum tolerated dose (MTD) cohort expansion must have
accessible tumor that can be biopsied with acceptable clinical risk (as judged by the
investigator) and must consent to a pre-treatment, week 0 and week 6 biopsy
(following two doses of ipilimumab); an optional biopsy at the time of progressive
disease will also be discussed however is not mandatory

- BOTH COHORTS:

- Patients must have measurable disease per RECIST 1.1, defined as at least one lesion
that can be accurately measured in at least one dimension (longest diameter to be
recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with
conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan,
magnetic resonance imaging (MRI), or calipers by clinical exam

- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

- Life expectancy of greater than 3 months

- Leukocytes >= 3 K/mcL

- Absolute neutrophil count >= 1.5 K/mcL

- Platelets >= 100 K/mcL

- Hemoglobin >= 8.0 g/dl

- Total bilirubin =< 1.5 x institutional upper limit of normal; note: patients with
hyperbilirubinemia clinically consistent with an inherited disorder of bilirubin
metabolism (e.g., Gilbert syndrome) will be eligible at the discretion of the
treating physician and/or the principal investigator

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

- Creatinine =< 1.5 x institutional upper limit of normal or creatinine clearance >= 60
mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

- 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 and
for the duration of study participation; should a woman become pregnant or suspect
she is pregnant while she or her partner is participating in this study, she should
inform her treating physician immediately; men treated or enrolled on this protocol
must also agree to use adequate contraception prior to the study, for the duration of
study participation, and 4 months after completion of dasatinib administration

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Patients who have had chemotherapy (non-tyrosine kinase inhibitor [TKI]) or
radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to
entering the study or those who have not recovered from adverse events due to agents
administered more than 4 weeks earlier

- Patients with a history of prior treatment with ipilimumab or dasatinib

- Patients who are receiving any other investigational agents

- Patients with known brain metastases are excluded from this clinical trial

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to dasatinib and ipilimumab

- Patients who require concurrent treatment with any medications or substances that are
potent inhibitors or inducers of cytochrome P450, family 3, subfamily A, polypeptide
4 (CYP3A4)

- Patients who require concurrent treatment with any medications or substances that
have significant proarrhythmic potential are ineligible

- Patients with 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 dasatinib tablets are excluded

- Patients may not have any clinically significant cardiovascular disease including the
following:

- Myocardial infarction or ventricular tachyarrhythmia within 6 months

- Prolonged QTc > 480 msec

- Ejection fraction less than 50%

- Major conduction abnormality (unless a cardiac pacemaker is present)

- Uncontrolled intercurrent illness including, but not limited to, the following:
ongoing or active infection; history of significant bleeding disorder, including
congenital (von Willebrand's disease) or acquired (anti-factor VIII antibodies)
disorders; large pleural effusions; or psychiatric illness/social situations that
would limit compliance with study requirements

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with dasatinib

- Subjects may not have known human immunodeficiency virus (HIV), active hepatitis A,
or hepatitis B or C infection

- Subjects with any active autoimmune disease or a documented history of autoimmune
disease or history of syndrome that required systemic steroids or immunosuppressive
medications including but not limited to inflammatory bowel disease, rheumatoid
arthritis, autoimmune thyroiditis, autoimmune hepatitis, systemic sclerosis
(scleroderma and variants), systemic lupus erythematosus, autoimmune vasculitis,
autoimmune neuropathies (e.g. Guillain-Barre syndrome), and multiple sclerosis;
patients with vitiligo, asthma and diabetes are NOT excluded; final determination can
be left to the discretion of the principal investigator

- Subjects may not have ongoing chronic diarrhea

- Subjects may not have had prior organ allograft or allogenic bone marrow
transplantation

- Subjects may not have any major surgery within 4 weeks

- Subjects may not have known current drug or alcohol abuse

- Subjects may not have an underlying medical condition that in the opinion of the
investigator could adversely affect the ability of the subject to comply with or
tolerate study procedures and/or study therapy, or confound the ability to interpret
the tolerability of combined administration of dasatinib and ipilimumab in treated
subjects

- Subjects may not have other active malignancies other than indolent malignancies not
requiring active therapy which the investigator determines are unlikely to interfere
with treatment and safety analysis

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Maximum tolerated dose (MTD) defined as the highest dose studied for which the observed incidence of dose-limiting toxicity (DLT) is less than 33% according to the National Cancer Institute (NCI) Common Toxicity Criteria

Outcome Time Frame:

Up to week 12

Safety Issue:

No

Principal Investigator

Richard Carvajal

Investigator Role:

Principal Investigator

Investigator Affiliation:

Memorial Sloan-Kettering Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2012-01165

NCT ID:

NCT01643278

Start Date:

July 2012

Completion Date:

Related Keywords:

  • Chondrosarcoma
  • Clear Cell Sarcoma of the Kidney
  • Endometrial Stromal Sarcoma
  • Ewing Sarcoma of Bone
  • Extraosseous Ewing Sarcoma
  • Gastrointestinal Stromal Tumor
  • Mast Cell Sarcoma
  • Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor
  • Metastatic Osteosarcoma
  • Ovarian Sarcoma
  • Recurrent Adult Soft Tissue Sarcoma
  • Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor
  • Recurrent Osteosarcoma
  • Recurrent Uterine Sarcoma
  • Stage III Adult Soft Tissue Sarcoma
  • Stage III Uterine Sarcoma
  • Stage IV Adult Soft Tissue Sarcoma
  • Stage IV Uterine Sarcoma
  • Chondrosarcoma
  • Osteosarcoma
  • Mast-Cell Sarcoma
  • Neuroectodermal Tumors
  • Neuroectodermal Tumors, Primitive
  • Sarcoma, Endometrial Stromal
  • Sarcoma, Clear Cell
  • Sarcoma
  • Adenoma
  • Gastrointestinal Stromal Tumors
  • Sarcoma, Ewing's
  • Neuroectodermal Tumors, Primitive, Peripheral

Name

Location

Memorial Sloan Kettering Cancer CenterNew York, New York  10021