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Carfilzomib and Hyper-CVAD in Treating Patients With Newly Diagnosed Acute Lymphoblastic Leukemia or Lymphoma

Primary Purpose

Contiguous Stage II Adult Lymphoblastic Lymphoma, Noncontiguous Stage II Adult Lymphoblastic Lymphoma, Stage I Adult Lymphoblastic Lymphoma

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

carfilzomib

cyclophosphamide

vincristine sulfate

doxorubicin hydrochloride

dexamethasone

methotrexate

cytarabine

leucovorin calcium

methylprednisolone

rituximab

laboratory biomarker analysis

About this trial

This is an interventional treatment trial for Contiguous Stage II Adult Lymphoblastic Lymphoma

Eligibility Criteria

18 Years - 64 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Understand and voluntarily sign an informed consent form
Able to adhere to the study visit schedule and other protocol requirements
Newly diagnosed acute lymphoblastic leukemia/lymphoma
Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (3 if it is directly disease related and is expected to get better if the acute lymphoblastic leukemia/lymphoma [ALL] is under control)
Left ventricular ejection fraction (LVEF) > 40%
Total bilirubin =< 3 mg/dL
Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.5 x upper limit of normal
Creatinine clearance (CrCl) >= 45 mL/minute within 7 days prior to enrollment either measured or calculated using a standard formula (eg, Cockcroft and Gault); in cases that creatinine clearance cannot be measured accurately, 24 hour urine can be used
Disease free of other malignancies beside the ALL at the time of the study
Male subjects must agree to practice contraception
Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 24 hours prior to the initiation of the study and they must agree to ongoing pregnancy testing and to practice contraception

Exclusion Criteria:

Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form
Pregnant or breast feeding females
Active congestive heart failure (New York Heart Association [NYHA] class III to IV), symptomatic ischemia, or conduction abnormalities uncontrolled by conventional intervention
Unstable angina or myocardial infarction within 6 months prior to enrollment, NYHA class III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or grade 3 conduction system abnormalities unless subject has a pacemaker
Uncontrolled hypertension, uncontrolled pulmonary hypertension or uncontrolled diabetes within 14 days prior to enrollment
Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to enrollment
Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study
Use of any other experimental drug or therapy within 14 days of baseline
Known history of allergy to Captisol®
Known sero-positive for active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV); patients who are sero-positive because of hepatitis B virus vaccine are eligible
Breakpoint cluster region-Abelson positive (BCR-ABL +) patients will be excluded from the study

Sites / Locations

University of California Davis

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (carfilzomib and hyper-CVAD)

Arm Description

Patients receive carfilzomib IV over 30 minutes on days 0, 1, 7, and 8. Patients also receive hyper-CVAD comprising cyclophosphamide IV over 2 hours every 12 hours for 6 doses beginning on day 1, vincristine sulfate IV on days 4 and 11, doxorubicin hydrochloride IV over 2-24 hours on day 4, and dexamethasone PO on days 1-4 and 11-14 (courses 1 and 3) and methotrexate IV over 24 hours on day 1, cytarabine IV over 2 hours every 12 hours for 4 doses starting on day 2, leucovorin calcium IV or PO every 6 hours beginning 36 hours after the start of methotrexate infusion, and methylprednisolone IV every 12 hours for 6 doses beginning on day 1 (courses 2 and 4). Patients with CD20 positive disease also receive rituximab twice daily on days 1 and 11 of courses 1 and 3 and days 1 and 8 of courses 2 and 4. Treatment repeats every 3-4 weeks for 4 courses in the absence of disease progression or unacceptable toxicity.

Outcomes

Primary Outcome Measures

Maximum tolerated dose of carfilzomib with hyper-CVAD, defined as the dose that produces dose limiting toxicity in 17% or fewer (1/6) of patients, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4

The toxicities observed at each dose level will be summarized in terms of type (organ affected or laboratory determination such as absolute neutrophil count), severity (by NCI CTCAE version 4.0) and nadir or maximum values for the laboratory measures, time of onset (i.e. course number), duration, and reversibility or outcome. Tables will be created to summarize these toxicities and side effects by dose and by course.

Secondary Outcome Measures

Rate of remission

All responses will be reported. Response rate among patients with measurable disease will be summarized by exact binomial confidence intervals.

Rate of minimal residual disease (MRD) in bone marrow aspirate samples

MRD will be defined an aberrant expression of at least 2 antigens in comparison with the known patterns of antigen expression by normal maturing CD19 positive B-cells. A distinct cluster of at least 20 cells showing altered antigen expression will be characterized as an aberrant cell population.

Rate of MRD in bone marrow aspirate samples

Full Information

NCT ID

NCT02293109

First Posted

November 13, 2014

Last Updated

March 8, 2022

Sponsor

Mehrdad Abedi, MD

Collaborators

Amgen

1. Study Identification

Unique Protocol Identification Number

NCT02293109

Brief Title

Carfilzomib and Hyper-CVAD in Treating Patients With Newly Diagnosed Acute Lymphoblastic Leukemia or Lymphoma

Official Title

Phase I Study of Escalating Doses of Carfilzomib With Hyper-CVAD in Patients With Newly Diagnosed Acute Lymphoblastic Leukemia/Lymphoma

Study Type

Interventional

2. Study Status

Record Verification Date

March 2022

Overall Recruitment Status

Completed

Study Start Date

December 17, 2015 (Actual)

Primary Completion Date

December 13, 2017 (Actual)

Study Completion Date

January 11, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Mehrdad Abedi, MD

Collaborators

Amgen

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

This phase I trial studies the side effects and best dose of carfilzomib when given together with the hyperfractionated (hyper)-cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone (CVAD) chemotherapy regimen in treating patients with newly diagnosed acute lymphoblastic leukemia or lymphoma. Carfilzomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving carfilzomib with combination chemotherapy may kill more cancer cells.

Detailed Description

PRIMARY OBJECTIVES: I. Safety and tolerability of administering carfilzomib in combination with hyper-CVAD chemotherapy. II. Recommended dose of carfilzomib in combination with hyper-CVAD chemotherapy for the future phase II trial. SECONDARY OBJECTIVES: I. Rate of remission after 2nd and 4th cycles. II. Incidence of minimal residual disease by flow cytometry at 4th cycle. OUTLINE: This is a dose escalation study of carfilzomib. Patients receive carfilzomib intravenously (IV) over 30 minutes on days 0, 1, 7, and 8. Patients also receive hyper-CVAD comprising cyclophosphamide IV over 2 hours every 12 hours for 6 doses beginning on day 1, vincristine sulfate IV on days 4 and 11, doxorubicin hydrochloride IV over 2-24 hours on day 4, and dexamethasone orally (PO) on days 1-4 and 11-14 (courses 1 and 3) and methotrexate IV over 24 hours on day 1, cytarabine IV over 2 hours every 12 hours for 4 doses starting on day 2, leucovorin calcium IV or PO every 6 hours beginning 36 hours after the start of methotrexate infusion, and methylprednisolone IV every 12 hours for 6 doses beginning on day 1 (courses 2 and 4). Patients with cluster of differentiation (CD)20 positive disease also receive rituximab twice daily on days 1 and 11 of courses 1 and 3 and days 1 and 8 of courses 2 and 4. Treatment repeats every 3-4 weeks for 4 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 28 days.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Contiguous Stage II Adult Lymphoblastic Lymphoma, Noncontiguous Stage II Adult Lymphoblastic Lymphoma, Stage I Adult Lymphoblastic Lymphoma, Stage III Adult Lymphoblastic Lymphoma, Stage IV Adult Lymphoblastic Lymphoma, Untreated Adult Acute Lymphoblastic Leukemia

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

10 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Treatment (carfilzomib and hyper-CVAD)

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

carfilzomib

Other Intervention Name(s)

Kyprolis, PR-171

Intervention Description

Given IV

Intervention Type

Drug

Intervention Name(s)

cyclophosphamide

Other Intervention Name(s)

CPM, CTX, Cytoxan, Endoxan, Endoxana

Intervention Description

Given IV

Intervention Type

Drug

Intervention Name(s)

vincristine sulfate

Other Intervention Name(s)

leurocristine sulfate, VCR, Vincasar PFS

Intervention Description

Given IV

Intervention Type

Drug

Intervention Name(s)

doxorubicin hydrochloride

Other Intervention Name(s)

ADM, ADR, Adria

Intervention Description

Given IV

Intervention Type

Drug

Intervention Name(s)

dexamethasone

Other Intervention Name(s)

Aeroseb-Dex, Decaderm, Decadron, DM, DXM

Intervention Description

Given PO

Intervention Type

Drug

Intervention Name(s)

methotrexate

Other Intervention Name(s)

amethopterin, Folex, methylaminopterin, Mexate, MTX

Intervention Description

Given IV

Intervention Type

Drug

Intervention Name(s)

cytarabine

Other Intervention Name(s)

ARA-C, arabinofuranosylcytosine, arabinosylcytosine, Cytosar-U, cytosine arabinoside

Intervention Description

Given IV

Intervention Type

Drug

Intervention Name(s)

leucovorin calcium

Other Intervention Name(s)

CF, CFR, LV

Intervention Description

Given IV or PO

Intervention Type

Drug

Intervention Name(s)

methylprednisolone

Other Intervention Name(s)

Depo-Medrol, Medrol, MePRDL, Solu-Medrol, Wyacort

Intervention Description

Given IV

Intervention Type

Biological

Intervention Name(s)

rituximab

Other Intervention Name(s)

IDEC-C2B8, IDEC-C2B8 monoclonal antibody, Mabthera, MOAB IDEC-C2B8, Rituxan

Intervention Type

Other

Intervention Name(s)

laboratory biomarker analysis

Intervention Description

Correlative studies

Primary Outcome Measure Information:

Title

Description

Time Frame

Up to 56 days (after second course)

Secondary Outcome Measure Information:

Title

Rate of remission

Description

All responses will be reported. Response rate among patients with measurable disease will be summarized by exact binomial confidence intervals.

Time Frame

Up to 56 days (after second course)

Title

Rate of minimal residual disease (MRD) in bone marrow aspirate samples

Description

Time Frame

Up to 56 days (after second course)

Title

Rate of MRD in bone marrow aspirate samples

Description

Time Frame

Up to 112 days (after 4th course)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

64 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Understand and voluntarily sign an informed consent form Able to adhere to the study visit schedule and other protocol requirements Newly diagnosed acute lymphoblastic leukemia/lymphoma Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (3 if it is directly disease related and is expected to get better if the acute lymphoblastic leukemia/lymphoma [ALL] is under control) Left ventricular ejection fraction (LVEF) > 40% Total bilirubin =< 3 mg/dL Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.5 x upper limit of normal Creatinine clearance (CrCl) >= 45 mL/minute within 7 days prior to enrollment either measured or calculated using a standard formula (eg, Cockcroft and Gault); in cases that creatinine clearance cannot be measured accurately, 24 hour urine can be used Disease free of other malignancies beside the ALL at the time of the study Male subjects must agree to practice contraception Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 24 hours prior to the initiation of the study and they must agree to ongoing pregnancy testing and to practice contraception Exclusion Criteria: Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form Pregnant or breast feeding females Active congestive heart failure (New York Heart Association [NYHA] class III to IV), symptomatic ischemia, or conduction abnormalities uncontrolled by conventional intervention Unstable angina or myocardial infarction within 6 months prior to enrollment, NYHA class III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or grade 3 conduction system abnormalities unless subject has a pacemaker Uncontrolled hypertension, uncontrolled pulmonary hypertension or uncontrolled diabetes within 14 days prior to enrollment Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to enrollment Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study Use of any other experimental drug or therapy within 14 days of baseline Known history of allergy to Captisol® Known sero-positive for active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV); patients who are sero-positive because of hepatitis B virus vaccine are eligible Breakpoint cluster region-Abelson positive (BCR-ABL +) patients will be excluded from the study

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Mehrdad Abedi

Organizational Affiliation

University of California, Davis

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of California Davis

City

Sacramento

State/Province

California

ZIP/Postal Code

95817

Country

United States

12. IPD Sharing Statement

Learn more about this trial

Carfilzomib and Hyper-CVAD in Treating Patients With Newly Diagnosed Acute Lymphoblastic Leukemia or Lymphoma

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