Bortezomib (VELCADE), Cladribine and Rituximab (VCR) in Mantle Cell Lymphoma (PSHCI 10-011) - Full Text View

Purpose

This is a phase I/II trial of bortezomib, cladribine, and rituximab in newly diagnosed and relapsed mantle cell lymphoma (MCL). The phase I component has three dose levels of cladribine (3 mg/m2, 4 mg/m2, and 5 mg/m2) and is designed as a traditional dose-escalation study in which cohorts of 3 patients are evaluated for the incidence of dose-liming toxicity (DLT) at each dose level. Once the maximum tolerated dose (MTD) is determined, a phase II component with 2 arms will begin. One arm will enroll newly diagnosed MCL patients and one arm will enroll relapsed MCL patients. Each arm is a single-stage, fixed sample size study and will be accrued and analyzed separately. The phase I and II data will also be analyzed separately.

Condition	Intervention	Phase
Mantle Cell Lymphoma	Drug: Rituximab Drug: bortezomib Drug: Cladribine	Phase 1 Phase 2

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Bortezomib (VELCADE), Cladribine and Rituximab (VCR) in Mantle Cell Lymphoma: A Phase I/II Study (PSHCI 10-011)

Resource links provided by NLM:

MedlinePlus related topics: Lymphoma

Drug Information available for: Cladribine Rituximab Bortezomib

U.S. FDA Resources

Further study details as provided by Penn State University:

Primary Outcome Measures:

Primary Outcome Dose Limiting Tolerability [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
Dose Limiting Tolerability as measured by CTCAEv.3 criteria and to evaluate progression free survival in patients treated with VCR in the Phase 1 portion .

Secondary Outcome Measures:

Secondary Outcome objective response rates [ Time Frame: 7 months ] [ Designated as safety issue: Yes ]
Estimate objective response rates of the VCR regimen in B cell malignancies where response to therapy is assessed per the revised Cheson criteria (2007) and the overall survival of patients treated with this combination for the Phase 2 portion of the study.

Estimated Enrollment:	50
Study Start Date:	May 2012
Estimated Study Completion Date:	October 2015
Estimated Primary Completion Date:	October 2014 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Phase I The phase I portion of the study is a standard dose-escalation schemed designed to determine the maximum tolerated dose (MTD) of cladribine in the combination of bortezomib, cladribine, and rituximab therapy. The MTD is defined as the dose level in which ≤1 out of 6 patients have dose-limiting toxicity (DLT).	Drug: Rituximab 376 mg/m2 on day 5, then on day 12, 19, 26 for the 1st cycle; then day 5 of cladribine for next 5 cycles, then every 2 months maintenance Other Name: Rituxam Drug: Cladribine Phase I will use 3 dose levels 3 mg/m2, 4 mg/m2, 5 mg/m2, with 3 mg/mg being the starting dose level.
Experimental: Phase II The phase II portion of the study is a two-arm, single-stage design with no interim analysis. One arm will accrue newly diagnosed patients, and one arm will accrue relapsed patients. In each arm, the progression-free survival rate at 2 years will be used as the primary endpoint for determining whether the treatment is sufficiently active in each arm. No comparisons will be made between the arms.	Drug: bortezomib 1.6 mg/m2 weekly on day 12, then on day 19 and 26 for 3 cycles. Then 1.6/mg/m2 every 2 weeks; start post cycle 3 of bortezomib Other Name: VELCADE

Arms

Assigned Interventions

Experimental: Phase I

The phase I portion of the study is a standard dose-escalation schemed designed to determine the maximum tolerated dose (MTD) of cladribine in the combination of bortezomib, cladribine, and rituximab therapy. The MTD is defined as the dose level in which ≤1 out of 6 patients have dose-limiting toxicity (DLT).

Drug: Rituximab

376 mg/m2 on day 5, then on day 12, 19, 26 for the 1st cycle; then day 5 of cladribine for next 5 cycles, then every 2 months maintenance

Other Name: Rituxam

Drug: Cladribine

Phase I will use 3 dose levels 3 mg/m2, 4 mg/m2, 5 mg/m2, with 3 mg/mg being the starting dose level.

Experimental: Phase II

The phase II portion of the study is a two-arm, single-stage design with no interim analysis. One arm will accrue newly diagnosed patients, and one arm will accrue relapsed patients. In each arm, the progression-free survival rate at 2 years will be used as the primary endpoint for determining whether the treatment is sufficiently active in each arm. No comparisons will be made between the arms.

Drug: bortezomib

1.6 mg/m2 weekly on day 12, then on day 19 and 26 for 3 cycles. Then 1.6/mg/m2 every 2 weeks; start post cycle 3 of bortezomib

Other Name: VELCADE

Detailed Description:

The phase I portion of the study is a standard dose-escalation schemed designed to determine the maximum tolerated dose (MTD) of the combination of bortezomib, cladribine, and rituximab therapy. The MTD is defined as the dose level in which ≤1 out of 6 patients have dose-limiting toxicity (DLT). Three patients are enrolled on a dose level. If 0 out of 3 patients have DLT, then the next set of 3 patients are enrolled at the next highest dose level. If ≥2 out of 3 patients have DLT, then the MTD will have been exceeded and dose escalation will cease. Three additional patients will be enrolled at the next lowest dose level if only 3 were treated previously at that level. If 1 out of 3 patients have DLT, then the next set of 3 patients will be treated at the same dose level. If ≤1 out of 6 patients treated at that dose level have DLT, then the next set of patients will be treated at the next higher dose level. If ≥2 out of 6 patients treated at that dose level have DLT, then the MTD will have been exceeded and dose escalation will cease. Three additional patients will be treated at the next lowest dose level if only 3 were treated previously at that level. This phase I study will use 3 dose levels of cladribine (3 mg/m2, 4 mg/m2, and 5 mg/m2), with 3 mg/m2 being the starting dose level. DLTs will be assessed at the completion of the first 2 cycles of cladribine and rituximab.

Phase II Design: The phase II portion of the study is a two-arm, single-stage design with no interim analysis. One arm will accrue newly diagnosed patients, and one arm will accrue relapsed patients. In each arm, the progression-free survival rate at 2 years will be used as the primary endpoint for determining whether the treatment is sufficiently active in each arm. No comparisons will be made between the arms.

Eligibility

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

Criteria

Inclusion Criteria:

Females that are postmenopausal for at least 1 year before the screening visit, surgically sterilized or if they are of childbearing potential agree to practice 2 effective methods of contraception from the time of signing the informed consent form through 30 days after the last dose.
Male subjects must agree to practice effective barrier contraception during the entire study treatment period and through a minimum of 30 days after the last dose of study drug, or completely abstain from heterosexual intercourse.
Patients with newly diagnosed and relapsed mantle cell lymphoma.
ECOG performance status grade 3 or higher.

Exclusion Criteria:

Patient has a platelet count of <50x10 9/L within 14 days before enrollment if not related to disease.
Patient has an absolute neutrophil count less than 100 within 14 days before enrollment if not related to disease.
Patient has a calculated or measured creatinine clearance of <20 mL/minute within 14 days before enrollment.
Patient has > Grade 2 peripheral neuropathy within 14 days before enrollment.
Patient has > 1.5 x ULN total bilirubin.
Myocardial infarction within 6 months prior to enrollment or has New York Heart Association Class II or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.
Patient has hypersensitivity to bortezomib, boron or mannitol.
Female subject is pregnant or breast-feeding.
Patient has received other investigational drugs within 14 days before enrollment.
Serious medical or psychiatric illness likely to interfere with participation in this clinical study.
Diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01439750

Locations

United States, Pennsylvania
Penn State Milton S. Hershey Medical Center
Hershey, Pennsylvania, United States, 17033
Penn State University
Hershey, Pennsylvania, United States, 17033

Sponsors and Collaborators

Penn State University

Investigators

Principal Investigator:

Elliot M Epner, MD PhD

Milton S. Hershey Medical Center

More Information

No publications provided

Responsible Party:	Elliot M. Epner, Professor of Medicine, Penn State University
ClinicalTrials.gov Identifier:	NCT01439750 History of Changes
Other Study ID Numbers:	PSHCI 10-011
Study First Received:	August 16, 2011
Last Updated:	May 10, 2013
Health Authority:	United States: Institutional Review Board

Keywords provided by Penn State University:

mantle cell lymphoma

Additional relevant MeSH terms:

Lymphoma
Lymphoma, Mantle-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Rituximab
Bortezomib

Cladribine
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on May 23, 2013