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Bortezomib, Isatuximab, Cyclophosphamide and Dexamethasone Induction in Transplant-Eligible Multiple Myeloma Patients

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04240054
Recruitment Status : Not yet recruiting
First Posted : January 27, 2020
Last Update Posted : July 1, 2020
Sponsor:
Information provided by (Responsible Party):
Binod Dhakal, Medical College of Wisconsin

Brief Summary:
This is a single-arm, open-label phase II study with a safety lead-in phase.

Condition or disease Intervention/treatment Phase
Multiple Myeloma Drug: Bortezomib Drug: Isatuximab Drug: Cyclophosphamide Drug: Dexamethasone Phase 2

Detailed Description:

The study hypothesis is that the isatuximab plus bortezomib, cyclophosphamide and dexamethasone (VCD) combination is safe and highly effective even in those with renal insufficiency (RI) from myeloma. In this study, we seek to improve the efficacy of VCD by adding isatuximab in newly diagnosed multiple myeloma patients undergoing autologous stem cell transplant (ASCT) irrespective of renal function.

The primary objective is to determine if the addition of isatuximab to VCD will increase the proportion of subjects achieving very good partial response (VGPR), as defined by the International Myeloma Working Group (IMWG) criteria and by the time of completion of post-ASCT consolidation treatment.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 41 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multisite, Phase II Study of Bortezomib, Isatuximab, Cyclophosphamide and Dexamethasone (VICD) Induction in Transplant-Eligible Multiple Myeloma Patients
Estimated Study Start Date : June 1, 2021
Estimated Primary Completion Date : December 1, 2023
Estimated Study Completion Date : December 1, 2024


Arm Intervention/treatment
Experimental: Safety Lead-in Cohort A

Six transplant-eligible multiple myeloma patients with renal impairment will be enrolled.

Bortezomib (1.5 mg/m^2) subcutaneous on days 1,8 and 15 Isatuximab (10 mg/kg) IV on days 1, 8, 15 and 22 Cyclophosphamide (250 mg/m^2) IV on days 1, 8 and 15 Dexamethasone 20 mg PO or IV (10 mg if >75 years) on days 1, 2, 8, 9,15,16, 22 and 23

Drug: Bortezomib
Bortezomib (1.5 mg/m^2) subcutaneous on days 1, 8 and 15
Other Name: Velcade

Drug: Isatuximab
Isatuximab (10 mg/kg) IV on days 1, 8, 15 and 22
Other Name: SAR650984

Drug: Cyclophosphamide
Cyclophosphamide (250 mg/m^2) IV on days 1, 8 and 15
Other Names:
  • Cytoxan
  • Neosar
  • cytophosphane

Drug: Dexamethasone
Dexamethasone 20 mg PO or IV (10 mg if >75 years) on days 1, 2, 8, 9, 15, 16, 22 and 23
Other Names:
  • Baycadron
  • Decadron
  • DexPak
  • TaperDex
  • Zema-Pak
  • ZoDex
  • Zonacort

Experimental: Expansion Cohort A

15 transplant-eligible multiple myeloma patients with renal impairment will be enrolled.

Bortezomib (1.5 mg/m^2)subcutaneous on days 1, 8 and 15 Isatuximab (10 mg/kg) IV on days 1, 8, 15 and 22 Cyclophosphamide (250 mg/m^2) IV on days 1, 8 and 15 Dexamethasone 20 mg PO or IV (10 mg if >75 years) on days 1, 2, 8, 9,15,16, 22 and 23

Drug: Bortezomib
Bortezomib (1.5 mg/m^2) subcutaneous on days 1, 8 and 15
Other Name: Velcade

Drug: Isatuximab
Isatuximab (10 mg/kg) IV on days 1, 8, 15 and 22
Other Name: SAR650984

Drug: Cyclophosphamide
Cyclophosphamide (250 mg/m^2) IV on days 1, 8 and 15
Other Names:
  • Cytoxan
  • Neosar
  • cytophosphane

Drug: Dexamethasone
Dexamethasone 20 mg PO or IV (10 mg if >75 years) on days 1, 2, 8, 9, 15, 16, 22 and 23
Other Names:
  • Baycadron
  • Decadron
  • DexPak
  • TaperDex
  • Zema-Pak
  • ZoDex
  • Zonacort

Experimental: Expansion Cohort B

20 transplant-eligible non-renal impairment multiple myeloma patients will be enrolled.

Bortezomib (1.5 mg/m^2) subcutaneous on days 1, 8 and 15 Isatuximab (10 mg/kg) IV on days 1, 8, 15 and 22 Cyclophosphamide (250 mg/m^2) IV on days 1, 8 and 15 Dexamethasone 20 mg PO or IV (10 mg if >75 years) on days 1, 2, 8, 9,15,16, 22 and 23

Drug: Bortezomib
Bortezomib (1.5 mg/m^2) subcutaneous on days 1, 8 and 15
Other Name: Velcade

Drug: Isatuximab
Isatuximab (10 mg/kg) IV on days 1, 8, 15 and 22
Other Name: SAR650984

Drug: Cyclophosphamide
Cyclophosphamide (250 mg/m^2) IV on days 1, 8 and 15
Other Names:
  • Cytoxan
  • Neosar
  • cytophosphane

Drug: Dexamethasone
Dexamethasone 20 mg PO or IV (10 mg if >75 years) on days 1, 2, 8, 9, 15, 16, 22 and 23
Other Names:
  • Baycadron
  • Decadron
  • DexPak
  • TaperDex
  • Zema-Pak
  • ZoDex
  • Zonacort




Primary Outcome Measures :
  1. The number of subjects who achieve very good partial response. [ Time Frame: 100 days following autologous stem cell transplant ]
    This will be measured using the International Myeloma Working Group criteria.


Secondary Outcome Measures :
  1. The number of subjects who achieve complete response. [ Time Frame: 100 following autologous stem cell transplant. ]
    This will be measured using the International Myeloma Working Group criteria.

  2. The number of subjects who achieve partial response. [ Time Frame: 100 days following autologous stem cell transplant. ]
    This will be measured using the International Myeloma Working Group criteria.

  3. The number of subjects who have a complete renal response. [ Time Frame: 100 days following autologous stem cell transplant. ]
    This will be measured using the International Myeloma Working Group criteria.

  4. The number of subjects who have a partial renal response. [ Time Frame: 100 days following autologous stem cell transplant. ]
    This will be measured using the International Myeloma Working Group criteria.

  5. The number of subjects who have a minor renal response. [ Time Frame: 100 days following autologous stem cell transplant. ]
    This will be measured using the International Myeloma Working Group criteria.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.
  2. Male or female subjects ≥18 years.
  3. Patients must be eligible for high-dose therapy and autologous stem cell transplantation as per institutional guidelines.
  4. No prior multiple myeloma (MM) -directed therapy except for dexamethasone (up to 160 mg), bortezomib (up to 5.2 mg/m2) and/or cyclophosphamide up to 500 mg/m2 administered for management of acute manifestations of MM (hypercalcemia, renal impairment, pain) for no longer than four weeks prior to enrollment. If subject received any prior therapy, pretreatment parameters necessary for disease characterization and response assessment (at least one of the following: Serum protein electrophoresis (SPEP)/Immunofixation electrophoresis (IFE), 24-hour urine protein with urine protein electrophoresis (UPEP)/ IFE, serum free light chains and bone marrow procedure) must be available.
  5. Patients must have documented multiple myeloma as defined by the criteria below (a, b, and c):

    1. Monoclonal plasma cells in the bone marrow of ≥10% or presence of a biopsy proven plasmacytoma AND
    2. Evidence of organ damage or myeloma-defining events (MDE) that can be attributed to the underlying proliferative plasma cell disorder (at least one of the following):

      • Hypercalcemia: serum calcium >1 mg/dL higher than the upper limit of normal (ULN) or >11 mg/Dl.

      OR

      • Anemia: hemoglobin value of >2.0 g/dL below the lower limit of normal, or a hemoglobin value <10.0 g/dL.

      OR

      • Bone marrow plasma cells of >60%. OR
      • Involved/uninvolved light chain ratio ≥100 OR
      • Renal insufficiency: creatinine clearance (CrCl) <40 mL/min (based on actual body weight; measured or estimated by validated equations and/or serum creatinine >177 μmol/L (>2 mg/dL) [Only Cohort A subjects must meet this criterion]
    3. Measurable disease as defined (at least one of the following):

      • Serum M-protein level ≥0.5 g/dL; OR
      • Urine M-protein level ≥200 mg/24 hours; OR
      • Light chain multiple myeloma without measurable disease in the urine: serum immunoglobulin (Ig) free light chains (FLC) ≥10 mg/dL and abnormal serum Ig kappa/lambda FLC ratio.
  6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
  7. Female subjects who:

    1. Are postmenopausal for at least one year before the screening visit, OR
    2. Are surgically sterile, OR
    3. Females of childbearing potential or male subjects with female partners of childbearing potential shall be required to use effective contraceptive methods (double barrier method, intrauterine device, oral contraception or abstinence) starting two weeks before first study drug(s) administration, while on therapy and for 16 weeks following the last dose of study drug(s). A woman is considered of childbearing potential, i.e., fertile, following menarche and until becoming postmenopausal unless permanently sterile. The following highly effective methods of contraception are accepted:

      • Established use of oral, intravaginal, or transdermal combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation.
      • Established use of oral, injectable, or implantable progestogen-only hormonal contraception associated with inhibition of ovulation.
      • Placement of an intrauterine device or intrauterine hormone-releasing system.
      • Barrier methods of contraception: male condom with either cap, diaphragm or sponge with spermicide (double-barrier methods). The use of double-barrier methods should always be supplemented with the use of a spermicide. Female condom and male condom should not be used together.
      • Male sterilization (provided that the partner is the sole sexual partner of the patient and that the sterilized partner has received medical assessment of the surgical success).
      • Sexual abstinence.
      • Female subjects must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction starting two weeks before first study drug(s) administration, while on therapy and for 16 weeks following the last dose of study drug(s).
  8. Male subjects, even if surgically sterilized (i.e., status postvasectomy), who:

    1. Agree to practice effective barrier contraception during the entire study treatment period from the time of signing the informed consent through and through four months after the last dose of study drug(s) (female and male condoms should not be used together), or
    2. Agree to practice true abstinence during the entire study treatment period from the time of signing the informed consent through 16 weeks after the last dose of study drug(s), when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods for the female partner] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.)

Exclusion Criteria:

  1. Diagnosed or treated for malignancy other than multiple myeloma, except:

    • Malignancy treated with curative intent and with no known active disease present for ≥3 years before enrollment.
    • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
    • Adequately treated carcinoma in situ (e.g., cervical, breast) with no evidence of disease.
  2. Exhibiting clinical signs of or has a known history of meningeal or central nervous system involvement by multiple myeloma.
  3. Known to be seropositive for human immunodeficiency virus, known to have hepatitis B surface antigen positivity, or known to have untreated or active hepatitis C.
  4. Concurrent medical condition or disease (e.g., active systemic infection) that is likely to interfere with study procedures or results, or that in the opinion of the investigator would constitute a hazard for participating in this study. Specifically, any potential subject who is unsuitable for ASCT would be excluded from the study.
  5. Clinically significant cardiac disease, including:

    • Myocardial infarction within six months before Cycle 1, Day 1, or unstable or uncontrolled disease/condition related to or affecting cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV).
    • Uncontrolled cardiac arrhythmia (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE] Version 5 Grade 2 or higher) or clinically significant electrocardiogram (ECG) abnormalities.
    • Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia's formula (QTcF) >470 msec.
    • Uncontrolled hypertension.
  6. Any of the following laboratory test results at the time of enrollment:

    • Absolute neutrophil count <1.0 × 109/L; no granulocyte colony stimulating factor (G-CSF) treatment in the past seven days are allowed.
    • Hemoglobin level ≤7.5 g/dL (≤5 mmol/L); blood transfusions to maintain hemoglobin >7.5 g/dL are acceptable.
    • Platelet count <75 × 109/L for subjects in whom <50% of bone marrow nucleated cells are plasma cells; otherwise platelet count <50 × 109/L; no platelet transfusions in the past seven days are allowed.
    • Alanine aminotransferase (ALT) level ≥2.5 × ULN
    • Aspartate aminotransferase (AST) level ≥2.5 × ULN
    • Total bilirubin level ≥1.5 × ULN, (except for Gilbert Syndrome: direct bilirubin ≥2 × ULN)
  7. Known allergies, hypersensitivity (if not amenable to premedication with steroids, or H2 blockers), or intolerance to monoclonal antibodies or human proteins, isatuximab or its excipients or known sensitivity to mammalian-derived products.
  8. Plasma cell leukemia (>2.0 × 10^9/L circulating plasma cells by standard differential), Waldenström's macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and/or skin changes), or light-chain amyloidosis.
  9. Known or suspected of not being able to comply with the study protocol (e.g., because of alcoholism, drug dependency, or psychological disorder) or the subject has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (e.g., compromise their well-being) or that could prevent, limit, or confound the protocol-specified assessments.
  10. Pregnant or breastfeeding or planning to become pregnant starting two weeks before first study drug(s) administration, while on therapy and for 16 weeks following the last dose of study drug(s).
  11. Plans to father a child starting two weeks before first study drug(s) administration, while on therapy and for 16 weeks following the last dose of study drug(s).
  12. Had major surgery within two weeks before Cycle 1, Day 1, or will not have fully recovered from surgery, or has surgery planned during the time the subject is expected to participate in the study or within two weeks after the last dose of study drug administration. Note: Subjects with planned surgical procedures to be conducted under local anesthesia are not excluded. Kyphoplasty is not considered a major surgery.
  13. Patients with pre-existing uncontrolled pulmonary disease will be excluded; uncontrolled refers to patients having had at least one hospitalization due to pulmonary disease (for example, asthma, chronic obstructive pulmonary disease) within the six months prior to enrollment in the study; patients with previous history of pneumonitis will be excluded.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04240054


Contacts
Layout table for location contacts
Contact: Medical College of Wisconsin Cancer Center Clinical Trials Office 414-805-8900 cccto@mcw.edu

Sponsors and Collaborators
Medical College of Wisconsin
Investigators
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Principal Investigator: Binod Dhakal, MD Medical College of Wisconsin
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Responsible Party: Binod Dhakal, Assistant Professor, Medical College of Wisconsin
ClinicalTrials.gov Identifier: NCT04240054    
Other Study ID Numbers: PRO00036788
First Posted: January 27, 2020    Key Record Dates
Last Update Posted: July 1, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Binod Dhakal, Medical College of Wisconsin:
Multiple Myeloma
Renal Insufficiency
Isatuximab
Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Dexamethasone
Cyclophosphamide
Bortezomib
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents