A Dose Escalation Study of the Combination of Lenalidomide (Revlimid®), Dexamethasone and Cyclophosphamide in Patients Refractory or Relapsing From Stable Disease With Multiple Myeloma (CRD)

A Phase I Dose Escalation Study of the Combination of Lenalidomide (Revlimid®), Dexamethasone and Cyclophosphamide in Patients Refractory or Relapsing From Stable Disease With Multiple Myeloma

The purpose of this study is to determine the maximum tolerated dose (MTD) and to evaluate the safety of cyclophosphamide when given on days 1 and 8 in a 28 day cycle in doses starting at 300mg ranging to 700mg in combination with Lenalidomide (Revlimid®) plus dexamethasone in patients who present with relapsed or refractory myeloma.

Study Overview

• Status: Completed
• Conditions: Multiple Myeloma
• Intervention / Treatment: Drug: Lenalidomide; Drug: Dexamethasone; Drug: Cyclophosphamide

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, SE5 9RS
    • King's College Hospital NHS Foundation Trust
  • London, United Kingdom, SM2 5PT
    • Royal Marsden NHS Foundation Trust

Participation Criteria

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:

1. Understand and voluntarily sign an informed consent form.
2. Age >18 years at the time of signing the informed consent form.
3. Proven diagnosis of multiple myeloma.
4. Relapse or Refractory disease with evidence of progression after at least 2 cycles of anti-myeloma treatment.
5. Relapse or refractory disease with evidence of progressive disease after at least 1 previous therapy this may include consolidation of induction with a stem cell transplant).
6. Subjects may have been previously treated with thalidomide and/or radiation therapy. In addition, radiation therapy initiated prior to or at baseline (Day 1) must be complete prior to the initiation of therapy. The initiation of radiation therapy after baseline (Day 1) will be considered to be a treatment failure (except when given to treat or to promote the healing of a pathological fracture).
7. Measurable levels of myeloma paraprotein in serum (>5 gms/L) or urine > 2 g excreted in a 24-hour collection sample).
8. Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2.
9. Able to adhere to the study visit schedule and other protocol requirements.
10. Women of childbearing potential (WCBP) must have a negative serum or urine pregnancy test within 10 - 14 days and again within 24 hours of starting study drug. In addition, sexually active WCBP must agree continued abstinence from heterosexual intercourse or to use adequate contraceptive methods starting 4 weeks prior to the initiation of therapy. WCBP must agree to have pregnancy tests weekly for the first 4 weeks, then monthly while on study drug (every 14 days for women with irregular cycles) and 4 weeks after the last dose of study drug. Men must also agree to use a condom if their partner is of child bearing potential, even if they have had a successful vasectomy.
11. Disease free of prior malignancies for equal to or over 5 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma "in-situ" of the cervix or breast.
12. Able to receive low dose aspirin (e.g. 75mg) as prophylactic anticoagulant medication to prevent thromboembolism unless contraindicated. If low dose aspirin is contraindicated, subjects will receive another form of anticoagulant prophylaxis according to hospital guidelines.

Exclusion Criteria:

1. Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form.
2. Pregnant or lactating females.

3. Any of the following laboratory abnormalities:

   1. Absolute neutrophil count (ANC) <1.000 cells/mm3 (1.0 x 109/L)
   2. Platelet count <.75.000/mm3 (75 x 109L)
   3. Serum creatinine >2.5 mg/dL (221 umol/L)
   4. Serum SGOT/AST or SGPT/ALT >3.0 x upper limit of normal (ULN)
   5. Serum total bilirubin >2.0 mg/dL (34 umol/L)
4. 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.
5. Known hypersensitivity to thalidomide, dexamethasone or cyclophosphamide.
6. Prior history of uncontrollable side effects to dexamethasone therapy
7. The development of a desquamating rash while taking thalidomide
8. Any prior use of Lenalidomide (Revlimid®)
9. Use of any standard/experimental anti-myeloma drug therapy within 28 days of entry or use of any experimental non-drug therapy (e.g. donor leukocyte/mononuclear cell infusions) within 56 days of entry.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: CRD

Drug: Lenalidomide; Oral lenalidomide 25mg daily on Days 1-21 every 28 days cycles for up to 9 cycles. From Cycle 10 Lenalidomide 25mg orally on days 1-21, every 28 days.; Other Names: Revlimid; Drug: Dexamethasone; Dexamethasone 20mgs orally, daily on Days 1-4 and 8-11 repeated every 28 day cycles for up to 9 cycles.; Drug: Cyclophosphamide; Oral Cyclophosphamide will be added to the regime starting on days 1 and 8. The dose of Cyclophosphamide will be escalated in cohorts rising in 100mg increments from 300 to 700mgs days 1,and 8 every 28 day cycles for up to 9 cycles.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Dose limiting toxicity defined as: a) NCI Grade 4 haematological toxicity b) NCI Grade ¾ non-haematological toxicity	Weekly for first cycle
Safety (type, frequency, severity, and relationship of adverse events)	Weekly for first cycle then monthly

Secondary Outcome Measures

Outcome Measure	Time Frame
Time to progression	Monthly
Paraprotein response	Monthly
Bone marrow response	Baseline, end of treatment and disease progression
Duration of response	Monthly
Overall survival	Monthly

Collaborators and Investigators

• Sponsor: King's College Hospital NHS Trust
• Investigators: Principal Investigator: Steve Schey, FRCP FRACP FRCPath, King's College Hospital NHS Trust

Study record dates

Study Major Dates

• Study Start: September 1, 2006
• Primary Completion (Actual): March 1, 2014
• Study Completion (Actual): March 1, 2014

Study Registration Dates

• First Submitted: June 5, 2009
• First Submitted That Met QC Criteria: June 5, 2009
• First Posted (Estimate): June 8, 2009

Study Record Updates

• Last Update Posted (Estimate): September 2, 2015
• Last Update Submitted That Met QC Criteria: September 1, 2015
• Last Verified: April 1, 2013

More Information

Terms related to this study

• Keywords: Multiple Myeloma; Lenalidomide; Cyclophosphamide; Dexamethasone
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Dexamethasone; Cyclophosphamide; Lenalidomide
• Other Study ID Numbers: 05CC15; REC - 06/Q1606/75; EudraCT - 2005-005145-19