Pom-dex Versus Pom-Cyclo-dex in MM Patients With Biochemical or Clinical Relapse, During Lena Maintenance Treatment

NCT03440411 | Terminated Phase 3 Results

• 1 other identifier: PO-CL-MM-PI-003887
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 1

Brief Summary

The combination lenalidomide plus low-dose dexamethasone (Rd) is an active treatment for Multiple Myeloma (MM) patients, both at diagnosis and at relapse. Pomalidomide, is an immunomodulatory molecule (IMID), derivative of thalidomide, developed to improve the efficacy and reduce the toxicity of the parent molecule. Pomalidomide and dexamethasone (pom-dex) proved to be an effective and safe treatment in MM patients refractory to lenalidomide and refractory/intolerant to bortezomib. The addition of chemotherapy to novel drugs has been evaluated both at diagnosis and at relapse. The combination of pomalidomide-cyclophosphamide-prednisone proved to be safe and effective in relapsed/refractory MM patients. The combination pomalidomide-cyclophosphamide-dexamethasone (pom-cyclo-dex) was tested in a phase II study in patients with relapsed and refractory MM, demonstrating a good tolerability using pomalidomide at the dose of 4 mg. Pom-cyclo-dex resulted in a superior response rate and Progression-Free Survival (PFS) compared to pom-dex. The increased hematologic toxicities, as a result of the addition of oral cyclophosphamide, were manageable. With an overall response rate of 65% the combination demonstrated a promising efficacy.The first aim of our trial, is to compare the combination of pom-cyclo-dex vs pom-dex. Relapsed myeloma is defined as previously treated myeloma that progresses and requires the initiation of salvage therapy. According to International Myeloma Working Group (IMWG) recommendation, biochemical relapse is defined as an increase of ≥ 25% of tumor burden from lowest value, without any CRAB feature (CRAB is defined as the onset of clinical symptoms: hypercalcemia, renal failure, anemia and bone lesions) and detected in 2 consecutive determinations. Clinical relapse requires one or more direct indicators of progressive disease and end organ dysfunction (CRAB features). Treatment at relapse should start in case of clinical relapse or a significant paraprotein increase (doubling of M-component in 2 months). In case of biochemical relapse the standard is observation only, as in case of asymptomatic MM at diagnosis. However, a recently published trial, showed improved PFS and OS for newly diagnosed asymptomatic patients treated with lenalidomide and dexamethasone in comparison with observation only. Our hypothesis is that similarly, in the relapse setting, patients may benefit from an early intervention, meaning a treatment at biochemical relapse and not only in case of clinical relapse or rapid increase of M-component.

Conditions

Multiple Myeloma

Keywords

biochemical relapse

Outcome Measures

Primary Outcomes (2)

• Overall Survival (OS)

  defined as the time from the date of random disclosure to the date of death from any cause for the comparisons B vs A

  57 months

• Overall Survival

  defined as the time from the date of random disclosure to the date of death from any cause for the comparisons II vs I

  57 months

Secondary Outcomes (9)

• Clinical Progression

  57 months

• Progression Free-survival (PFS)

  57 months

• Progression Free Survival (PFS)

  57 months

• Progression Free-survival 2(PFS2)

  57 months

• Progression Free Survival 2(PFS2)

  57 months

Study Arms (4)

ARM pom-dex Early (A-I)

ACTIVE COMPARATOR

Patients will receive treatment at biochemical relapse with pom-dex Pomalidomide: 4 mg/day on days 1-21 Dexamethasone: 40 mg on days 1, 8, 15, 22 For 28-day cycles until progression or intolerance

Drug: Pomalidomide; Drug: Dexamethasone

ARM pom-cyclo-dex Early(B-I)

EXPERIMENTAL

Patients will receive treatment at biochemical relapse with pom-cyclo-dex Pomalidomide: 4 mg/day on days 1-21 Cyclophosphamide: 50 mg every other day Dexamethasone: 40 mg on days 1, 8, 15, 22 For 28-day cycles until progression or intolerance

Drug: Pomalidomide; Drug: Cyclophosphamide; Drug: Dexamethasone

ARM pom-dex Late (A-II)

EXPERIMENTAL

Patients will be randomized at biochemical relapse and they will start treatment with pom-dex at the onset of CRAB symptoms/significant paraprotein increase. Pomalidomide: 4 mg/day on days 1-21 Dexamethasone: 40 mg on days 1, 8, 15, 22 For 28-day cycles until progression or intolerance

Drug: Pomalidomide; Drug: Dexamethasone

ARM pom-cyclo-dex Late (B-II)

ACTIVE COMPARATOR

Patients will be randomized at biochemical relapse and they will start treatment with pom-cyclo-dex at the onset of CRAB symptoms/significant paraprotein increase. Pomalidomide: 4 mg/day on days 1-21 Cyclophosphamide: 50 mg every other day Dexamethasone: 40 mg on days 1, 8, 15, 22 For 28-day cycles until progression or intolerance

Drug: Pomalidomide; Drug: Cyclophosphamide; Drug: Dexamethasone

Interventions

Pomalidomide DRUG

4 mg/daily as oral administration (PO) on days 1-21.

Also known as: Imnovid(R)

ARM pom-cyclo-dex Early(B-I); ARM pom-cyclo-dex Late (B-II); ARM pom-dex Early (A-I); ARM pom-dex Late (A-II)

Cyclophosphamide DRUG

50 mg every other day as oral administration (PO) on days 1-28

Also known as: Endoxan(R)

ARM pom-cyclo-dex Early(B-I); ARM pom-cyclo-dex Late (B-II)

Dexamethasone DRUG

40 mg as oral administration (PO) on days 1, 8, 15, 22.

Also known as: Soldesam(R)

ARM pom-cyclo-dex Early(B-I); ARM pom-cyclo-dex Late (B-II); ARM pom-dex Early (A-I); ARM pom-dex Late (A-II)

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients \>18 years and \<80 years.
• Patient is, in the investigator(s) opinion, willing and able to comply with the protocol requirements.
• Patient has given 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 patient at any time without prejudice to their future medical care.
• Male patient agrees to use an acceptable method for contraception (i.e. condom or abstinence) for the duration of the study.
• Female of childbearing potential agrees to use two acceptable methods for contraception \[implant, levonorgestrel-releasing intrauterine system (IUS), medroxyprogesterone acetate depot, tubal sterilization, sexual intercourse with a vasectomised male partner only (vasectomy must be confirmed by two negative semen analyses), ovulation inhibitory progesterone-only pills (i.e. desogestrel)\] or absolute and continuous sexual abstinence.
• Patient has measurable disease, defined as follows: any quantifiable serum monoclonal protein value (generally, but not necessarily, ≥ 0.5 g/dL of M-protein) and, where applicable, urine light-chain excretion of \>200 mg/24 hours; only in patients without measurable serum and urine M-protein levels: the difference between involved and uninvolved Free Light Chain (FLC) levels must be \> 10 mg/dL. Less than 10% of oligo- or non-secretory MM patients with free light chains will be admitted to this study in order to maximize interpretation of benefit results.
• Patient receiving lenalidomide maintenance therapy as part of first line treatment (concomitant use of prednisone is accepted) and has experienced a biochemical relapse, with evidence of progressive disease defined as an increase of 25% from lowest response value in any one or more of the following: serum M-component (absolute increase must be ≥0.5 g/100 ml) and/or urine M-component (absolute increase must be ≥200 mg per 24 hours) only in patients without measurable serum and urine M-protein levels: the difference between involved and uninvolved FLC levels must be \>10 mg/dL (35).
• Patient who received as first line treatment a bortezomib-based therapy, including lenalidomide maintenance during the same line of therapy, can be included in the trial.
• Patient has a life-expectancy \> 3 months
• Patient has not a currently active malignancy, other than non melanoma skin cancer and carcinoma in situ of the cervix, and has not invasive malignancies within the past 5 years.
• No history of allergic reactions attributed to study agents
• Patient has the following laboratory values within 28 days before baseline day 1 of the cycle 1:
• absolute neutrophil count (ANC) \> 1 x 10\^9/L
• platelet count \> 75 x 10\^9/L
• haemoglobin \> 8 g/dl.

You may not qualify if:

• Pregnant or lactating females.
• Patient with Creatinine Clearance (CrCl) \< 45 mL/minute
• Patient with peripheral neuropathy ≥ Grade 2
• Subject with any one of the following:
• Congestive heart failure (NY Heart Association Class III or IV)
• Myocardial infarction within 12 months prior to starting study treatment
• Unstable or poorly controlled angina pectoris, including Prinzmetal variant angina pectoris
• Any significant medical disease or conditions (e.g. pulmonary disease, infection) that, in the investigator's opinion, may interfere with protocol adherence or subject's ability to give informed consent or could place the subject at unacceptable risk.
• Clinical active infectious hepatitis type A, B, C or HIV Acute active infection requiring antibiotics or infiltrative pulmonary disease
• Contraindication to any of the required drugs or supportive treatments.
• Known allergy to any of the study medications, their analogues, or excipients in the various formulations

Sponsors & Collaborators

• Fondazione EMN Italy Onlus: lead

Study Sites (1)

Fondazione EMN Italy Onlus

Torino, 10126, Italy

Location

MeSH Terms

Conditions

Multiple Myeloma

Interventions

pomalidomide; Cyclophosphamide; Dexamethasone

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Limitations and Caveats

Main limitations is that the sample size of participants needed to achieve target power and statistically reliable results was not reach. And no statistical testing was performed.

Results Point of Contact

• Title: Fondazione EMN Italy Onlus
• Organization: Fondazione EMN Italy Onlus

clinicaltrialoffice@emnitaly.org

+39 011 0243236

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is a 2x2 factorial randomized study.

Study Record Dates

• First Submitted: February 7, 2018
• First Posted: February 22, 2018
• Study Start: February 18, 2016
• Primary Completion: December 31, 2019
• Study Completion: December 31, 2019
• Last Updated: March 10, 2021
• Results First Posted: March 10, 2021

Record last verified: 2021-02

Locations

IT (1)