Clinical trial NCT01729338: Velcade + Cyclophosphamide in Newly Diagnosed Multiple Myeloma
Official title: Phase II Subcutaneous VELCADE and Oral Cyclophosphamide-based Induction + Sequential VELCADE and Revlimid Maintenance for Newly Diagnosed Multiple Myeloma in Non-transplant Candidates: An Entirely Non-intravenous Regimen
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Multiple Myeloma
Lead sponsor: Duke University
Sponsor class: OTHER
Collaborators: name: Millennium Pharmaceuticals, Inc.
name: Duke Cancer Institute
First posted: 2012-11-20
Enrollment: 17
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The primary purpose of this study is to estimate the overall response rate (ORR), defined as partial response (PR) or better at any time during induction therapy. The success of the therapy will be determined by ORR with strong consideration given to the secondary endpoints of tolerability, duration of response, and quality of life (QOL).

All patients will be treated with the same experimental regimen. Several novel features are being explored: the substitution of cyclophosphamide for melphalan; once weekly AND subcutaneous bortezomib instead of standard twice weekly, intravenous dosing; and alternating bortezomib and lenalidomide in maintenance.

The investigators hypothesize that this regimen will prove to be tolerable and effective in inducing and maintaining remission in a patient population that is historically very difficult to treat, namely Multiple Myeloma (MM) patients who are too elderly or suffer comorbidities, such as renal insufficiency, that otherwise complicate aggressive therapies like autologous stem-cell transplantation (ASCT). In short, the investigators view this as the "Multiple Myeloma trial for non-trial candidates."

Detailed description: A total of 35 patients will be accrued to this single arm, open label, phase II trial over a period of about 18 months, studying induction chemotherapy with VELCADE, cyclophosphamide and dexamethasone administered on an attenuated dosing schedule to accommodate non-candidates for high-dose chemotherapy with autologous stem cell transplantation - an often frail patient population. Maintenance therapy will follow with alternating lenalidomide and VELCADE. All patients should receive antiviral (zoster) prophylaxis, and peptic ulcer prophylaxis is recommended. Aspirin and/or anticoagulation are left to study physician discretion. All patients will be treated with the same experimental regimen. Several novel features are being explored: the substitution of cyclophosphamide for melphalan; once weekly AND subcutaneous bortezomib instead of standard twice weekly, intravenous dosing; and alternating bortezomib and lenalidomide in maintenance. The overarching aim is to preserve efficacy while minimizing toxicity and inconvenience to this often frail patient population.

Eligibility criteria: Inclusion Criteria:

* Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.
* Age ≥18 years at the time of signing the informed consent form.
* Able to adhere to the study visit schedule and other protocol requirements.
* Multiple Myeloma (MM) diagnosed according to the following standard criteria (all three criteria must be met):

  * Monoclonal plasma cells in bone marrow ≥10% and/or presence of biopsy-proven plasmacytoma
  * Laboratory tests meet the levels specified in the protocol
* Measurable disease requiring systemic therapy.
* No prior systemic therapy or radiation therapy active against myeloma lasting more than four weeks duration. Any prior therapy must be completed a minimum of 21 days before starting study drugs. Enrollment of subjects who require radiotherapy (which must be localized in its field size) should be deferred until the radiotherapy is completed and 3 weeks have elapsed since the last date of therapy.
* Karnofsky performance status (KPS) of ≥ 60% at study entry.
* In order to obtain lenalidomide, patients must be registered into the mandatory RevlimidREMS® program during the maintenance phase of therapy, and be willing and able to comply with the requirements of RevlimidREMS®
* Female subjects must be postmenopausal for at least 1 year before the screening visit or surgically sterilized. If females are of childbearing potential, they must adhere to required pregnancy testing; male and female subjects must use specified effective birth control methods.
* Patients should receive concomitant therapy with bisphosphonates, regardless of the presence of bony lesions, although study physicians may use their discretion based on presence of renal insufficiency or other mitigating factors.

Exclusion Criteria:

* Abnormal laboratory tests within the ranges specified in the protocol
* Serum creatinine will not be used to exclude patients. Patients on renal-replacement therapy (e.g., hemodialysis or peritoneal dialysis) will be eligible to participate.
* Light-chain (AL) amyloidosis. Patients with secondary amyloidosis due to MM are eligible.
* ≥ Grade 2 peripheral neuropathy
* Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any Electrocardiography (ECG) abnormality at screening must be documented by the investigator as not medically relevant.
* Hypersensitivity to VELCADE, boron, mannitol, or any other component of protocol therapy.
* Female subject is pregnant or lactating. Confirmation that the subject is not pregnant must be established by a negative serum beta-human chorionic gonadotropin (b- hCG) pregnancy test result obtained during screening as specified in section 7.11.
* Female patients who are lactating or have a positive serum pregnancy test during the screening period, or a positive urine pregnancy test on Day 1 before first dose of study drug, if applicable.
* Serious medical or psychiatric illness likely to interfere with participation in this clinical study.
* Diagnosed or treated for another malignancy within 2 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.
* Participation in clinical trials with other investigational agents not included in this trial, within 14 days of the start of this trial and throughout the duration of this trial.
* Concurrent use of other anti-cancer agents or treatments
* Known HIV positivity
* Known active hepatitis A, B or C

Primary outcomes:
measure: Overall Response Rate (ORR) During Induction Therapy
timeFrame: Up to 8 months
Secondary outcomes:
measure: Severe Adverse Event Rate
timeFrame: Up to 3 years
measure: Maximum Depth of Response During Induction Therapy
timeFrame: Up to 8 months
measure: Maximum Depth of Response During Maintenance Therapy
timeFrame: Up to 3 years
measure: Median Time to Response
timeFrame: Up to 8 months
measure: Median Duration of Response
timeFrame: From date of first confirmed response until date of disease progression or up to 3 years
measure: Median Progression-free Survival
timeFrame: 4 years
measure: Median Overall Survival
timeFrame: Up to 3 years
measure: QLQ-C30 Question 29
timeFrame: baseline, 3 months, 5 months
measure: QLQ-C30 Question 30
timeFrame: baseline, 3 months, 5 months
measure: Functionality as Assessed Using the Cancer and Leukemia Group B (CALGB) Geriatric Assessment Tool
timeFrame: baseline
measure: Risk Score as Assessed Using the Cancer and Leukemia Group B (CALGB) Geriatric Assessment Tool
timeFrame: Day 1
Other outcomes:
Locations:
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
Study officials:
affiliation: Duke University
name: Gwynn Long, MD
role: PRINCIPAL_INVESTIGATOR
References: