Everolimus, Bortezomib and/or Rituximab in Patients With Relapsed/Refractory Waldenstrom's Macroglobulinemia

NCT01125293 | Terminated Phase 1 Results DMC

• 3 other identifiers: 09-280R01FD003743; X05310R01FD003743
• Study Type: interventional
• Target: 46
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this research study is to test the safety of the combination of everolimus, rituximab and bortezomib. Everolimus is a drug that works by preventing cells in your body from growing and dividing. Information from basic and other clinical research suggests that everolimus may also inhibit tumor growth in people with relapsed or refractory lymphoma. The FDA has approved everolimus for the treatment of multiple myeloma, a cancer that is closely related to Waldenstrom's Macroglobulinemia. Rituximab is approved by the FDA for the treatment of non-Hodgkin's lymphoma, which included Waldenstrom's Macroglobulinemia. Funding Source - FDA OOPD

Conditions

Waldenstrom's Macroglobulinemia

Keywords

everolimus; rituximab; bortezomib; RAD001; Rituxan; Velcade

Outcome Measures

Primary Outcomes (4)

• Everolimus Maximum Tolerated Dose (MTD) Stage A [Phase I]

  The MTD of Everolimus/Rituximab combination is determined by the number of patients who have dose limiting toxicity (DLT). See DLT primary outcome measure for definition. MTD is defined as the highest dose where \<1/3 participants experience a DLT. If no DLT's are observed on Level 1, 3 subjects will be enrolled in the Level 2. If \>1/3 subjects in a cohort have DLT, that dose will not be considered safe, with no escalation (MTD exceeded). If 1/3 subjects experience DLT, the cohort will be expanded to 6 subjects. If \<2 subjects with a DLT among the expanded cohort of 6 evaluable subjects a cohort of 3 subjects will be enrolled in the next higher dose level. If 2 or more subjects with a DLT among the expanded cohort of 6 subjects, that dose level will not be considered safe, no escalation (MTD exceeded). If no DLT's are observed, then the MTD is not reached. The MTD was not reached with 0/3 participants experiencing a DLT in the highest dose level. Higher doses were not planned/tested.

  Assessed within the first cycle (28 days) of the study.

• Everolimus Maximum Tolerated Dose (MTD) Stage B [Phase I]

  The MTD of Everolimus/Bortezomib/Rituximab combination is determined by the number of patients who have dose limiting toxicity (DLT). See DLT primary outcome measure for definition. MTD is defined as the highest dose where \<1/3 participants experience a DLT. If no DLT's are observed on Level 1, 3 subjects will be enrolled in the Level 2. If \>1/3 subjects in a cohort have DLT, that dose will not be considered safe, with no escalation (MTD exceeded). If 1/3 subjects experience DLT, the cohort will be expanded to 6 subjects. If \<2 subjects with a DLT among the expanded cohort of 6 evaluable subjects a cohort of 3 subjects will be enrolled in the next higher dose level. If 2 or more subjects with a DLT among the expanded cohort of 6 subjects, that dose level will not be considered safe, no escalation (MTD exceeded).If no DLT's observed, then the MTD is not reached. The MTD was not reached with 0/3 participants experiencing a DLT in the highest level. Higher doses were not planned/tested.

  Assessed within the first cycle (28 days) of the study.

• Everolimus Dose Limiting Toxicity (DLT) [Phase I]

  The following qualify as dose limiting toxicities: * Grade 3 or greater non-hematologic toxicity, considered by the investigator to be related to study drugs. * Grade 4 hematologic toxicity defined as: thrombocytopenia with platelets \<10,000 µ/L on more than one occasion despite transfusion support; grade 4 neutropenia occurring for more than 7 days and/or resulting in neutropenic fever with elevated temperature (defined as \> 101 degrees F). Lymphopenia, a recognized side effect of bortezomib, is not considered a DLT. * Inability to receive Day 1 dose for Cycle 2 due to toxicity

  Assessed within the first cycle (28 days) of the study.

• Very-good-partial-response-or-better Rate [Phase II]

  Very-good-partial-response-or-better rate is the percentage of participants with complete response (CR) or very good partial response (VGPR) on to the combination of everolimus/bortezomib/rituximab. The combination regimen was received for up to 6 cycles. CR: * Absence of serum monoclonal IgM protein by immunofixation * Normal serum IgM level * Complete resolution of extramedullary disease, i.e., lymphadenopathy and splenomegaly if present at baseline * Morphologically normal bone marrow aspirate and trephine biopsy VGPR: * Monoclonal IgM protein is detectable ≥90% reduction in serum IgM level from baseline\* * Complete resolution of extramedullary disease, i.e.

  Up to 6 cycles (Day 168)

Secondary Outcomes (6)

• Treatment-Emergent Sensory Neuropathy Rate [Phase I]

  Adverse events were assessed each cycle (ever 28 days) for 6 cycles then every 3 months on maintenance. Duration of therapy for the Phase I study up to 41 months.

• Phase II Overall Response Rate

  Up to 6 cycles (Day 168)

• 2-year Time-to-progression Probability (TTP) [Phase II]

  Patients were assessed for disease every cycle while on treatment (168 days) and every three months while on maintenance therapy. In long-term follow-up, disease was monitored every 3 months. Study cohort median (range) follow-up was 15 (1 - 23) months.

• 2 Year Progression-free-survival [Phase II]

  Patients were assessed for disease every cycle while on treatment (168 days) and every three months while on maintenance therapy. In long-term follow-up, disease was monitored every 3 months. Study cohort median (range) follow-up was 15 (1 - 23) months.

• Phase II Duration of Response (DoR)

  Patients were assessed for disease every cycle while on treatment (168 days) and every three months while on maintenance therapy. In long-term follow-up, disease was monitored every 3 months. Study cohort median (range) follow-up was 15 (1 - 23) months.

Study Arms (6)

Phase I Stage A Level 1

EXPERIMENTAL

Combination of everolimus \& rituximab for 6 cycles: Everolimus 5 mg: Taken orally on a daily basis x 28 days Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only (1 cycle = 28 days) Maintenance: Everolimus 10 mg: Taken orally on a daily basis x 28 days (1 cycle = 28 days) Participants are treated on everolimus maintenance until progression, unacceptable toxicity or withdrawal for other reasons.

Drug: Everolimus; Drug: Rituximab

Phase I Stage A Level 2

EXPERIMENTAL

Combination of everolimus \& rituximab for 6 cycles: Everolimus 10 mg: Taken orally on a daily basis x 28 days Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only (1 cycle = 28 days) Maintenance: Everolimus 10 mg: Taken orally on a daily basis x 28 days (1 cycle = 28 days) Participants are treated on everolimus maintenance until progression, unacceptable toxicity or withdrawal for other reasons.

Drug: Everolimus; Drug: Rituximab

Phase I Stage B Level 1

EXPERIMENTAL

Combination of everolimus \& rituximab with bortezomib for 6 cycles: Everolimus 5 mg: Taken orally on a daily basis x 28 days Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only Bortezomib 1.6 mg/m\^2: Given intravenously on days 1, 8 and 15 of every cycle (1 cycle = 28 days) Maintenance: Everolimus 10 mg: Taken orally on a daily basis x 28 days (1 cycle = 28 days) Participants are treated on everolimus maintenance until progression, unacceptable toxicity or withdrawal for other reasons.

Drug: Everolimus; Drug: Rituximab; Drug: Bortezomib

Phase I Stage B Level 2

EXPERIMENTAL

Combination of everolimus \& rituximab with bortezomib for 6 cycles: Everolimus 10 mg: Taken orally on a daily basis x 28 days Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only Bortezomib 1.6 mg/m\^2: Given intravenously on days 1, 8 and 15 of every cycle (1 cycle = 28 days) Maintenance: Everolimus 10 mg: Taken orally on a daily basis x 28 days (1 cycle = 28 days) Participants are treated on everolimus maintenance until progression, unacceptable toxicity or withdrawal for other reasons.

Drug: Everolimus; Drug: Rituximab; Drug: Bortezomib

Phase I Dose Expansion

EXPERIMENTAL

Combination of everolimus \& rituximab with bortezomib for 6 cycles: Everolimus 10 mg: Taken orally on a daily basis x 28 days Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only Bortezomib 1.6 mg/m\^2: Given intravenously on days 1, 8 and 15 of every cycle (1 cycle = 28 days) Maintenance: Everolimus 10 mg: Taken orally on a daily basis x 28 days (1 cycle = 28 days) Participants are treated on everolimus maintenance until progression, unacceptable toxicity or withdrawal for other reasons.

Drug: Everolimus; Drug: Rituximab; Drug: Bortezomib

Phase II

EXPERIMENTAL

Combination of everolimus \& rituximab with bortezomib for 6 cycles: Everolimus 10 mg: Taken orally on a daily basis x 28 days Rituximab 375 mg/Kg: Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only Bortezomib 1.6 mg/m\^2: Given intravenously on days 1, 8 and 15 of every cycle Maintenance: Everolimus 10 mg: Taken orally on a daily basis x 28 days (1 cycle = 28 days) Participants are treated on everolimus maintenance until progression, unacceptable toxicity or withdrawal for other reasons.

Drug: Everolimus; Drug: Rituximab; Drug: Bortezomib

Interventions

Everolimus DRUG

Also known as: RAD001

Phase I Dose Expansion; Phase I Stage A Level 1; Phase I Stage A Level 2; Phase I Stage B Level 1; Phase I Stage B Level 2; Phase II

Rituximab DRUG

Also known as: Rituxan

Phase I Dose Expansion; Phase I Stage A Level 1; Phase I Stage A Level 2; Phase I Stage B Level 1; Phase I Stage B Level 2; Phase II

Bortezomib DRUG

Also known as: Velcade, PS-341

Phase I Dose Expansion; Phase I Stage B Level 1; Phase I Stage B Level 2; Phase II

Eligibility Criteria

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

You may qualify if:

• years of age or older
• Patients must have received prior therapies for their WM and have relapsed or refractory WM requiring therapy. Any number of prior therapies is acceptable. Patients must not have been refractory to rituximab. The last rituximab must be at least 3 months prior to the start of treatment. Prior treatment with bortezomib and/or everolimus is permitted.
• Measurable monoclonal IgM protein in the serum OR measurable quantitative immunoglobulin M (serum IgM).
• Lymphoplasmacytic cells in the bone marrow during any previous bone marrow biopsy.
• CD20 positive disease based on any previous bone marrow immuno-histochemistry or flow cytometric analysis performed prior to enrollment.
• ECOG Performance Status 0, 1 or 2
• Laboratory values as outlined in the protocol
• Capable of swallowing intact study medication tablets
• Life expectancy of 12 weeks or greater

You may not qualify if:

• Uncontrolled infection
• Other active malignancies
• Cytotoxic chemotherapy 3 weeks or less, or biologic or targeted novel therapy 2 weeks or less, or corticosteroids 2 weeks or less, or radiation therapy 2 weeks or less, or any ancillary treatment considered investigation 2 weeks or less, prior to registration. Patients may be receiving chronic corticosteroids if they are being given for disorders other than WM.
• Pregnant women, nursing women, men or women of childbearing potential who are unwilling to employ adequate contraception throughout the trial and for 8 weeks after the last dose of study treatment.
• Known to be HIV positive, or Hepatitis B positive. If the status of HIV is not known and patients are not at risk, then patients will not be specifically tested for HIV. Patients will be tested for Hepatitis B at time of screening. If patients are not considered high risk and have been vaccinated at an earlier date, results of the test are not required at the time of registration. For patients that are high risk, results must be obtained prior to registration.
• Patient has Grade 2 or higher peripheral neuropathy within 14 days of enrollment
• Diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of complete resection fo basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.
• Severely impaired lung function
• Uncontrolled diabetes
• Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis
• Impairment of gastrointestinal function or gastrointestinal disease
• Patients with active, bleeding diathesis
• Myocardial infarction within 6 months prior to enrollment or had NYHA Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.
• Hypersensitivity to everolimus or other rapamycins or to is excipients
• Patients who may need or are receiving live vaccines for immunization

Sponsors & Collaborators

• Dana-Farber Cancer Institute: lead
• Novartis: collaborator
• Millennium Pharmaceuticals, Inc.: collaborator

Study Sites (1)

Dana-Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

Related Publications (1)

• Ghobrial IM, Redd R, Armand P, Banwait R, Boswell E, Chuma S, Huynh D, Sacco A, Roccaro AM, Perilla-Glen A, Noonan K, MacNabb M, Leblebjian H, Warren D, Henrick P, Castillo JJ, Richardson PG, Matous J, Weller E, Treon SP. Phase I/II trial of everolimus in combination with bortezomib and rituximab (RVR) in relapsed/refractory Waldenstrom macroglobulinemia. Leukemia. 2015 Dec;29(12):2338-46. doi: 10.1038/leu.2015.164. Epub 2015 Jul 3.

  PMID: 26139427 RESULT

MeSH Terms

Conditions

Waldenstrom Macroglobulinemia

Interventions

Everolimus; Rituximab; Bortezomib

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; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Pyrazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Irene Ghobrial
• Organization: Dana-Farber Cancer Institute

irene_ghobrial@dfci.harvard.edu

617-632-4101

Study Officials

• Irene Ghobrial, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: March 16, 2010
• First Posted: May 18, 2010
• Study Start: April 1, 2010
• Primary Completion: December 1, 2013
• Study Completion: August 1, 2014
• Last Updated: April 23, 2021
• Results First Posted: April 23, 2021

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)