Chemotherapy Plus Sargramostim in Treating Patients With Refractory Myeloid Cancer

January 8, 2013 updated by: National Cancer Institute (NCI)

Dose Finding Study of Bryostatin-1 and GM-CSF in Refractory Myeloid Malignancies

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

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

35

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Maryland
      • Baltimore, Maryland, United States, 21287-8936
        • Johns Hopkins University

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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.
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Names:
  • pharmacological studies
Drug: bryostatin 1
Given IV
Other Names:
  • B705008K112
  • BRYO
  • Bryostatin
Biological: sargramostim
Given subcutaneously
Other Names:
  • Leukine
  • Prokine
  • GM-CSF

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
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
56 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Cancer Institute (NCI)

Investigators

  • Principal Investigator: B. Smith, Johns Hopkins University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

March 1, 2001

Primary Completion (Actual)

January 1, 2010

Study Registration Dates

First Submitted

March 3, 2001

First Submitted That Met QC Criteria

January 26, 2003

First Posted (Estimate)

January 27, 2003

Study Record Updates

Last Update Posted (Estimate)

January 9, 2013

Last Update Submitted That Met QC Criteria

January 8, 2013

Last Verified

January 1, 2013

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NCI-2012-03159
  • P01CA015396 (U.S. NIH Grant/Contract)
  • J0051

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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