Chemotherapy Plus Sargramostim in Treating Patients With Refractory Myeloid Cancer

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00012376
First received: March 3, 2001
Last updated: January 8, 2013
Last verified: January 2013
  Purpose

Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Colony-stimulating factors such as sargramostim may increase the number of immune cells found in bone marrow or peripheral blood and may help a person's immune system recover from the side effects of chemotherapy. Phase I trial to study the effectiveness of bryostatin 1 combined with sargramostim in treating patients who have refractory myeloid cancer


Condition Intervention Phase
Accelerated Phase Chronic Myelogenous Leukemia
Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
Adult Acute Myeloid Leukemia With Del(5q)
Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)
Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
Blastic Phase Chronic Myelogenous Leukemia
Chronic Myelomonocytic Leukemia
Chronic Phase Chronic Myelogenous Leukemia
Paroxysmal Nocturnal Hemoglobinuria
Previously Treated Myelodysplastic Syndromes
Recurrent Adult Acute Myeloid Leukemia
Refractory Anemia
Refractory Anemia With Ringed Sideroblasts
Relapsing Chronic Myelogenous Leukemia
Thrombocytopenia
Untreated Adult Acute Myeloid Leukemia
Drug: bryostatin 1
Biological: sargramostim
Other: laboratory biomarker analysis
Other: pharmacological study
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Dose Finding Study of Bryostatin-1 and GM-CSF in Refractory Myeloid Malignancies

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • MTD defined as the dose at which the CRM estimates that 30% of patients will experience dose-limiting toxicity (DLT) assessed using CTC version 2.0 [ Time Frame: 56 days ] [ Designated as safety issue: Yes ]

Enrollment: 35
Study Start Date: March 2001
Primary Completion Date: January 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (bryostatin 1 and sargramostim)
Patients receive bryostatin 1 IV continuously and GM-CSF subcutaneously once daily on days 1-21. Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients with disease stabilization or improvement may continue treatment for up to 12 courses.
Drug: bryostatin 1
Given IV
Other Names:
  • B705008K112
  • BRYO
  • Bryostatin
Biological: sargramostim
Given subcutaneously
Other Names:
  • GM-CSF
  • Leukine
  • Prokine
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the maximally tolerated dose of continuous intravenous infusion bryostatin-1 when given in combination with GM-CSF.

II. To describe and quantify the frequency of toxicity of the combination of continuous intravenous infusion bryostatin-1 and subcutaneously administered GM-CSF.

SECONDARY OBJECTIVES:

I. To describe the impact of the combination of bryostatin-1 and GM-CSF on the differentiation and cell cycle distribution of myeloid cells in vivo.

II. To describe the impact of the combination of bryostatin-1 and GM-CSF on T lymphocyte populations.

III. To assess the pharmacokinetics of continuous infusion bryostatin-1.

OUTLINE: This is a dose-escalation study of bryostatin 1.

Patients receive bryostatin 1 IV continuously and sargramostim (GM-CSF) subcutaneously once daily on days 1-21. Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients with disease stabilization or improvement may continue treatment for up to 12 courses.

Cohorts of 2 patients receive escalating doses of bryostatin 1 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which 30% of patients experience dose-limiting toxicity.

PROJECTED ACCRUAL: A maximum of 45 patients will be accrued for this study within 12-18 months.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • The diagnosis of MDS must be confirmed by a bone marrow aspirate and/or biopsy revealing refractory anemia, or primary refractory leukopenia or thrombocytopenia with morphologic features of MDS; patients with 5q- syndrome are ineligible; patients with RA and RARS are eligible provided they are transfusion dependent. Patients with chronic myelomonocytic leukemia (CMMoL) are eligible; allogeneic BMT will be the treatment priority for patients with HLA-matched siblings; MDS patients for whom intensive chemotherapy has failed to achieve remission will be candidates for this trial if the chemotherapy was administered > 1 month prior to enrollment, and performance status is adequate; patients are also eligible having previously progressed on other institutional trials, including phenylbutyrate and ATRA or 5'-azacytadine
  • Patients must have a bone marrow aspirate or biopsy confirmed diagnosis of relapsed AML within 4 weeks of registering for this trial; patients will be eligible only if their WBC is < 30 x 103/:l and stable for at least 7 days, and if they are unlikely to require cytotoxic therapy during the duration of the trial; patients may not have APL
  • Newly diagnosed patients may be considered for this trial provided they do not qualify for potentially curative intensive chemotherapeutic regimens; patients with APL are not eligible for this trial; patients who have refused chemotherapy for untreated AML, or who are deemed to be poor candidates medically for AML induction chemotherapy, but otherwise meet the criteria list below may enroll on this trial
  • Patients with accelerated or myeloid blast phase CML are eligible if their blast count is < 30 x 103/:L and stable for at least 7 days; patients previously treated for chronic phase CML will be eligible for this protocol; patients may also have undergone treatment for acceleration or blastic phase provided this is not within 2 weeks of enrollment and they meet all the eligibility criteria
  • All patients with PNH will be eligible provided they are experiencing symptoms associated with their disease; in particular, patients experiencing life-threatening complications of their illness, including abdominal, central vein or cerebral thromboses, active infections, as well as recurrent, symptomatic hemolytic crises and do not have other treatment options are encouraged to consider participation
  • JHOC confirmed and documented diagnosis of either AML, MDS, CML in accelerated or blast phase or PNH
  • Patients must have relatively stable bone marrow function for more than ten days prior to enrollment on the study; WBC count doubling within this time period would indicate unstable bone marrow function
  • ECOG performance status of 0, 1, 2
  • Patients must have central intravenous access; acceptable access include: PICC lines, hickman and hohn catheters, and port-a-caths
  • Patient or caregiver must be willing to perform subcutaneous injection
  • Serum creatinine < 2.0 mg/dL
  • Total serum bilirubin =< 1.6 mg/dL, unless secondary to hemolysis
  • SGOT/SGPT each < 2 times the upper limit of normal unless disease related (i.e., PNH, extramedullary disease)
  • Hemoglobin should be at least 8 gm/dL at the time of protocol entry; patients may receive transfusions to achieve this level
  • Patients must not have received treatment for their myeloid disorder within 2 weeks of beginning the trial; treatments include the use of chemotherapy, hematopoietic growth factors, and biologic therapy such as monoclonal antibodies; the exception is the use of hydroxyurea for patients with WBC > 10 x 103/:L; this duration of time appears adequate for wash out due to the relatively short-acting nature of most anti-leukemia agents
  • Patients must have recovered from all toxicities (to grade 0 or 1) associated with previous treatment
  • Patients must not have any clinical symptoms of active CNS disease; if CNS disease is suspected, patient must have LP with negative cytology
  • Patients must not have evidence of pulmonary leukostasis (i.e., the clinical syndrome associated with symptomatic shortness of breath or hypoxia which is directly attributed to an elevated white blood cell count and the resulting capillary ischemia) or disseminated intravascular coagulation (i.e., the clinical syndrome associated with systemic intravascular clotting which is directly attributed to excessive procoagulants that overwhelm the inhibitory arm of the coagulation cascade)
  • All women of potential child bearing must have negative serum B-HCG and use an effective means of birth control throughout the trial period
  • Patients must be able to provide informed consent and to return to clinic for adequate follow up as required by the protocol

Exclusion Criteria:

  • Diagnosis of RA with 5q- syndrome
  • Leukemia with blast count > 30 x 103/:L, uncontrolled with hydroxyurea
  • APL
  • CML in lymphoid blast phase
  • ECOG performance status >= 3
  • Patients with untreated positive blood cultures or radiographic evidence of active infections
  • Patients with active CNS disease
  • Patients with a previous history of intolerance to GM-CSF
  • Pregnant or lactating women are not eligible for this protocol; all patients with child-bearing potential must use effective contraception
  • Patients who have received bryostatin-1 in the past are not eligible for this protocol
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00012376

Locations
United States, Maryland
Johns Hopkins University
Baltimore, Maryland, United States, 21287-8936
Sponsors and Collaborators
Investigators
Principal Investigator: B. Smith Johns Hopkins University
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00012376     History of Changes
Other Study ID Numbers: NCI-2012-03159, J0051, P01CA015396
Study First Received: March 3, 2001
Last Updated: January 8, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Congenital Abnormalities
Anemia
Anemia, Refractory
Blast Crisis
Hemoglobinuria
Leukemia
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Leukemia, Myeloid, Accelerated Phase
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Myeloid, Chronic-Phase
Leukemia, Myelomonocytic, Chronic
Hemoglobinuria, Paroxysmal
Myelodysplastic Syndromes
Preleukemia
Leukemia, Myelomonocytic, Acute
Thrombocytopenia
Hematologic Diseases
Bone Marrow Diseases
Neoplasms by Histologic Type
Neoplasms
Cell Transformation, Neoplastic
Neoplastic Processes
Myeloproliferative Disorders
Pathologic Processes
Proteinuria
Urination Disorders
Urologic Diseases
Urological Manifestations
Signs and Symptoms

ClinicalTrials.gov processed this record on July 22, 2014