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A Study to Determine Dose and Tolerability of CC-220 Monotherapy, in Combination With Dexamethasone, and in Combination With Dexamethasone and Daratumumab or Bortezomib in Subjects With Relapsed and Refractory Multiple Myeloma (MM)

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ClinicalTrials.gov Identifier: NCT02773030
Recruitment Status : Recruiting
First Posted : May 16, 2016
Last Update Posted : December 3, 2018
Sponsor:
Information provided by (Responsible Party):
Celgene

Brief Summary:
This is a multicenter, multicountry, open-label, Phase 1b/2a dose-escalation study to determine the maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D) of CC-220 when administered as monotherapy (Cohort A) and in combination with dexamethasone (DEX) (Cohort B). The study will consist of a dose-escalation portion (Part 1) as well as an expansion of these two cohorts (ie, Cohort C: MonoT and Cohort D: DoubleT) at the RP2D to further evaluate safety and estimate preliminary efficacy (Part 2). The study will also establish the MTD/RP2D of CC- 220 when administered in combination with DARA and DEX (Cohort E) and in combination with BTZ and DEX (Cohort F).

Condition or disease Intervention/treatment Phase
Multiple Myeloma Drug: CC-220 Drug: Dexamethasone Drug: Daratumumab Drug: Bortezomib (BTZ) Phase 1 Phase 2

Detailed Description:

Subjects assigned to CC-220 monotherapy, who develop progressive disease (PD) will have the option to receive DEX in addition to CC-220 after consultation with the Medical Monitor. The dose of CC-220 will not be higher than the dose of CC-220 used in combination with dexamethasone in Cohort B that has been determined to be safe. Progressive disease must be confirmed in accordance with international myeloma working group (IMWG) criteria.

The starting dose of DEX will be 40 mg for subjects who are ≤75 years of age and 20 mg for subjects who are >75 years of age, given once weekly. This treatment will continue until PD, unacceptable toxicity or the subject withdraws consent.

For Cohorts A and B, the starting dose level of CC-220, dose level 1, is 0.3 mg. A dose level -1, of 0.15 mg, may also be evaluated if the starting dose level of 0.3 mg for 21 days of a 28-day cycle is not tolerated. For Cohorts E and F, the starting dose level of CC-220, dose level 1, is one dose level below the maximum dose for Cohort B that has been determined to be safe by the dose escalation committee (DEC) at the start of enrollment for both cohorts. For Cohort E in addition to CC-220 and DEX, daratumumab will be administered intravenously (IV) at a 16mg/kg dose. For Cohort F in addition to CC-220 and DEX, bortezomib will be administered subcutaneous (SC) at a 1.3mg/m2 dose.

All subjects with a minimal response (MR) or better who discontinue study treatment in Part 1 or Part 2 of the study for a reason other than PD or withdrawal of consent from the study will be followed for response assessment every 28 days (every 21 days for Cohort F) until PD.

The study will be conducted in compliance with the International Council for Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good Clinical Practice (GCP) and applicable regulatory requirements.

The initiation of Part 2 will begin when the RP2D is established in Part 1 in either Cohort A or Cohort B. Either cohort may begin once the RP2D is determined for each cohort independently during Part 1. All expansion decisions will be determined by the DEC after review of all safety, PK, biomarker and preliminary efficacy data, as applicable. During Part 2, the Independent Expert Reviewer will review safety data and any other data deemed relevant so that subject safety is ensured.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 154 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b/2a Multicenter, Open-Label, Dose-Escalation Study to Determine the Maximum Tolerated Dose, Assess the Safety And Tolerability, Pharmacokinetics And Preliminary Efficacy of CC-220 Monotherapy, in Combination With Dexamethasone, and in Combination With Dexamethasone and Daratumumab or Bortezomib in Subjects With Relapsed and Refractory Multiple Myeloma
Actual Study Start Date : October 14, 2016
Estimated Primary Completion Date : March 16, 2021
Estimated Study Completion Date : January 14, 2023


Arm Intervention/treatment
Experimental: Cohort A: CC-220 Monotherapy - Part 1
Oral CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day cycle
Drug: CC-220
CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day cycle.

Experimental: Cohort B: CC-220 in combination with Dexamethasone - Part 1
  • Oral CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day cycle.
  • For subjects ≤ 75 years old, oral DEX 40 mg on Days 1, 8, 15, and 22 of each 28-day cycle. For subjects >75 years old, DEX will be administered at 20 mg on Days 1, 8,15, and 22 of each 28-day cycle. Subjects who surpass the age of 75 years while on treatment may be switched to the 20 mg QD dosage based on the investigator's best judgment.
Drug: CC-220
CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day cycle.

Drug: Dexamethasone

Oral DEX 40 mg on Days 1, 8, 15, and 22 of each 28-day cycle. For subjects >75 years old, oral DEX will be administered at 20 mg on Days 1, 8, 15, and 22 of each 28-day cycle.

For Cohort F, DEX will be given on Days 1, 8, and 15 of each 21-day cycle.

Other Name: Decadron

Experimental: Cohort C: CC-220 Monotherapy - Part 2
Oral CC-220 at Recommended Phase 2 dose (RP2D) from Day 1-21 of each 28-day cycle
Drug: CC-220
CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day cycle.

Experimental: Cohort D: CC-220 in combination with Dexamethasone - Part 2
  • Oral CC-220 at Recommended Phase 2 dose (RP2D) from Day 1-21 of each 28-day cycle
  • Oral DEX 40 mg on Days 1, 8, 15, and 22 of each 28-day cycle. For subjects >75 years old, DEX will be administered at 20 mg on Days 1, 8, 15, and 22 of each 28-day cycle.
Drug: CC-220
CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day cycle.

Drug: Dexamethasone

Oral DEX 40 mg on Days 1, 8, 15, and 22 of each 28-day cycle. For subjects >75 years old, oral DEX will be administered at 20 mg on Days 1, 8, 15, and 22 of each 28-day cycle.

For Cohort F, DEX will be given on Days 1, 8, and 15 of each 21-day cycle.

Other Name: Decadron

Experimental: Cohort E: CC-220 with DEX and daratumumab (DARA) - Part 1

Oral CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day cycle.

  • Oral DEX for subjects ≤ 75 years old at 40 mg on Days 1, 8, 15, and 22 of each 28-day cycle. For subjects >75 years old, oral DEX at 20 mg on Days 1, 8, 15, and 22 of each 28-day cycle.
  • Intravenous DARA at dose 16 mg/kg on Days 1, 8, 15, and 22 at cycle 1-2, Days 1, 15 at cycle 3-6, and Day 1 at cycle ≥7 of each 28-day cycle.
Drug: CC-220
CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day cycle.

Drug: Dexamethasone

Oral DEX 40 mg on Days 1, 8, 15, and 22 of each 28-day cycle. For subjects >75 years old, oral DEX will be administered at 20 mg on Days 1, 8, 15, and 22 of each 28-day cycle.

For Cohort F, DEX will be given on Days 1, 8, and 15 of each 21-day cycle.

Other Name: Decadron

Drug: Daratumumab
Daratumumab (DARA) 16mg/kg by intravenous infusion on Days 1, 8, 15, and 22 at cycle 1-2, Days 1, 15 at cycle 3-6, and Day 1 at cycle ≥7 of each 28-day cycle.
Other Name: Darzalex

Experimental: Cohort F: CC-220 with DEX and bortezomib - Part 1

Oral CC-220 at dose specified by cohort dose level from Day 1-14 of each 21-day cycle.

  • Oral DEX for subjects ≤ 75 years old at 40 mg on Days 1, 8, and 15 of each 21-day cycle. For subjects >75 years old, oral DEX at 20 mg on Days 1, 8, and 15 of each 21-day cycle.
  • Subcutaneous BTZ at dose 1.3 mg/m^2 on Days 1, 4, 8 and 11 at cycle 1-8, and Days 1, 8 at cycle ≥9 of each 21-day cycle.
Drug: CC-220
CC-220 at dose specified by cohort dose level from Day 1-21 of each 28-day cycle.

Drug: Dexamethasone

Oral DEX 40 mg on Days 1, 8, 15, and 22 of each 28-day cycle. For subjects >75 years old, oral DEX will be administered at 20 mg on Days 1, 8, 15, and 22 of each 28-day cycle.

For Cohort F, DEX will be given on Days 1, 8, and 15 of each 21-day cycle.

Other Name: Decadron

Drug: Bortezomib (BTZ)
Bortezomib 1.3 mg/m^2 on Days 1, 4, 8 and 11 at cycle 1-8, and Days 1, 8 at cycle ≥9 of each 21-day cycle.
Other Name: Velcade




Primary Outcome Measures :
  1. Maximum Tolerated Dose (MTD) [ Time Frame: Approximately 1 year ]
    MTD is defined as the previous dose level where a Dose Limiting Toxicity (DLT) is observed in at least 2 subjects within the first cycle.

  2. Dose Limiting Toxicity (DLT) [ Time Frame: Approximately 1 year ]
    Number of participants with a DLT

  3. Establish Recommended Phase 2 doses (RP2Ds) [ Time Frame: Approximately 1 year ]
    RP2D is defined as the dose selected for the phase 2 portion of the trial.


Secondary Outcome Measures :
  1. Adverse Events (AEs) [ Time Frame: Approximately 3 years ]
    Number of participants with adverse events

  2. Overall response rate (ORR) [ Time Frame: Approximately 3 years ]
    Will be calculated as the number of responders divided by the number of subjects in the Efficacy Evaluable (EE) Population.

  3. Time to Response (TTR) [ Time Frame: Approximately 3 years ]
    Is defined as the time from the first date of dosing of IP to the first date of documented response (PR or better).

  4. Duration of Response (DOR) [ Time Frame: Approximately 3 years ]
    Is defined as Time from the first documentation of response to the first documentation of Progressive disease (PD)

  5. Pharmacokinetics ‐AUC 0-τ [ Time Frame: Approximately 1 year ]
    Area under the plasma concentration-time curve from time zero to tau, where tau is the dosing interval

  6. Pharmacokinetics ‐Cmax [ Time Frame: Approximately 1 year ]
    Maximum plasma concentration of drug

  7. Pharmacokinetics ‐Tmax [ Time Frame: Approximately 1 year ]
    Time to Maximum plasma concentration of drug

  8. Pharmacokinetics ‐t1/2 [ Time Frame: Approximately 1 year ]
    Terminal-phase elimination half life

  9. Pharmacokinetics ‐CLss/F [ Time Frame: Approximately 1 year ]
    Apparent total plasma clearance when dosed daily

  10. Pharmacokinetics ‐Vss/F [ Time Frame: Approximately 1 year ]
    Apparent total volume of distribution at steady state when dosed orally

  11. Progression-free Survival (PFS) [ Time Frame: Approximately 3 years ]
    Time from the first dose of investigational product (IP) to the first documentation of PD or death from any cause, whichever occurs first

  12. Overall Survival [ Time Frame: Approximately 3 years ]
    Time from first dose of IP to death due to any cause



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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:

Subjects must satisfy the following criteria to be enrolled in the study:

  1. Subject is ≥18 years of age at the time of signing the informed consent form (ICF)
  2. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted
  3. Subject is willing and able to adhere to the study visit schedule and other protocol requirements
  4. Subjects must have a documented diagnosis of Multiple myeloma (MM) and have measurable disease defined as:

    1. M-protein (serum and/or urine protein electrophoresis (sPEP) or (uPEP): sPEP ≥0.5 g/dL or uPEP ≥200 mg/24 hours and/or
    2. Light chain Multiple Myeloma without measurable disease in the serum or urine: serum immunoglobulin free light chain ≥ 10 mg/dL (100 mg/L) and abnormal serum immunoglobulin kappa lambda free light chain ratio.
  5. Subjects in Cohorts A to E must have received at least 2 prior myeloma regimens (note: induction with or without bone marrow transplant and with or without maintenance therapy is considered one regimen). Subjects in Cohort F must have received at least 1 prior myeloma regimen
  6. All subjects must have received prior treatment with at least 2 consecutive cycles of a lenalidomide or pomalidomide-containing regimen
  7. All subjects must have received prior treatment with at least 2 consecutive cycles of a proteasome inhibitor or a proteasome inhibitor-containing regimen
  8. For Part 2 (Cohort C and Cohort D), all subjects must have received prior treatment with at least 2 consecutive cycles of an anti-CD38 therapy or an anti-CD38-containing regimen
  9. All subjects must have documented disease progression on or within 60 days from the last dose of their last myeloma therapy
  10. Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2
  11. A female of childbearing potential (FCBP) is a female who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy, or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has not had menses at any time in the preceding 24 consecutive months) and must:

    1. Have two negative pregnancy tests as verified by the Investigator prior to starting study treatment. She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. This applies even if the subject practices true abstinence* from heterosexual contact.
    2. Either commit to true abstinence* from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with two forms of contraception: one highly effective, and one additional effective (barrier) measure of contraception without interruption 28 days prior to starting investigational product, during the study treatment (including dose interruptions), and for at least 28 days after the last dose of CC-220 or 90 days after the last dose of DARA (for Cohort E) or BTZ (for Cohort F). whichever is longer.
  12. Male subjects must:

    a. Practice true abstinence* (which must be reviewed on a monthly basis and source documented) or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 90 days following the last dose of study treatment, even if he has undergone a successful vasectomy.

    * True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. [Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.]

  13. Males must agree to refrain from donating sperm while on study treatment, during dose interruptions and for at least 90 days following last dose of study treatment.
  14. All subjects must agree to refrain from donating blood while on study treatment, during dose interruptions and for at least 28 days following the last dose of treatment.
  15. All male and female subjects must follow all requirements defined in the Pregnancy Prevention Program (v5.1).

Exclusion Criteria:

The presence of any of the following will exclude a subject from enrollment:

  1. Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study
  2. Subject has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study
  3. Subject has any condition that confounds the ability to interpret data from the study
  4. Subject has nonsecretory or oligosecretory multiple myeloma
  5. Subjects with Plasma Cell leukemia or amyloidosis
  6. Any of the following laboratory abnormalities

    • Absolute neutrophil count (ANC) <1,000/μL
    • Platelet count <75,000/μL
    • Corrected serum calcium >13.5 mg/dL (>3.4 mmol/L)
    • Serum glutamic oxaloacetic transaminase (SGOT)/aspartate aminotransferase (AST) or serum glutamic pyruvic transaminase (SGPT)/alanine aminotransferase (ALT) ≥2.0 x upper limit of normal (ULN)
    • Serum total bilirubin and alkaline phosphatase >1.5 x Upper Limit of Normal (ULN)
    • Subjects with serious renal impairment (24-hour creatinine clearance [CrCl] <50 mL/min) or requiring dialysis would be excluded
  7. Subjects with peripheral neuropathy ≥Grade 2
  8. Subjects with gastrointestinal disease that may significantly alter the absorption of CC-220
  9. Subjects with a prior history of malignancies, other than MM, unless the subject has been free of the disease for ≥5 years with the exception of the following noninvasive malignancies:

    • Basal cell carcinoma of the skin
    • Squamous cell carcinoma of the skin
    • Carcinoma in situ of the cervix
    • Carcinoma in situ of the breast
    • Incidental histological findings of prostate cancer such as T1a or T1b using the Tumor/Node/Metastasis (TNM) classification of malignant tumors or prostate cancer that is curative
  10. Subject has a history of anaphylaxis or hypersensitivity to thalidomide, lenalidomide, pomalidomide, DEX, daratumumab (for Cohort E), or bortezomib (for Cohort F)
  11. Subject has known or suspected hypersensitivity to the excipients contained in the formulation of CC-220, DEX, daratumumab (for Cohort E), or bortezomib (for Cohort F)
  12. Subject has received any of the following within the last 14 days of initiating IP:

    • Plasmapheresis
    • Major surgery (as defined by the Investigator)
    • Radiation therapy other than local therapy for MM associated bone lesions
    • Use of any systemic myeloma drug therapy
  13. Subject has been treated with an investigational agent (ie, an agent not commercially available) within 28 days or 5 half-lives (whichever is longer) of initiating investigational product (IP)
  14. Subject has any one of the following:

    • Clinically significant abnormal electrocardiogram (ECG) finding at Screening
    • Congestive heart failure (New York Heart Association Class III or IV)
    • Myocardial infarction within 12 months prior to starting IP
    • Unstable or poorly controlled angina pectoris, including the Prinzmetal variant of angina pectoris
  15. Subject has current or prior use of immunosuppressive medication within 14 days prior to the first dose of IP. The following are exceptions to this criterion:

    • Intranasal, inhaled, topical or local steroid injections (eg, intra-articular injection)
    • Systemic corticosteroids at physiologic doses that do not exceed 10 mg/day of prednisone or equivalent
    • Steroids as premedication for hypersensitivity reactions (eg, computed tomography [CT] scan premedication)
  16. Subject has taken a strong inhibitor or inducer of CYP3A4/5 including grapefruit, St. John's Wort or related products within two weeks prior to dosing and during the course of study
  17. Subject known to test positive for human immunodeficiency virus (HIV), chronic or active hepatitis B, or active hepatitis A or C
  18. Subject is unable or unwilling to undergo protocol required thromboembolism prophylaxis
  19. Subject is a female who is pregnant, nursing or breastfeeding or who intends to become pregnant during the participation in the study.

    Additional Exclusion Criteria for Cohort E (CC-220 + DARA + DEX):

  20. Subject has known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) 50% of predicted normal. Note that forced expiratory testing (FEV1) is required for subjects suspected of having COPD and subjects must be excluded if FEV1 is < 50% of predicted normal
  21. Subject has received previous allogeneic stem cell transplant; or received autologous stem cell transplantation within 12 weeks prior to enrollment
  22. Subject has known moderate or severe persistent asthma, or currently has uncontrolled asthma of any classification

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): NCT02773030


Contacts
Contact: Associate Director Clinical Trial Disclosure 1-888-260-1599 clinicaltrialdisclosure@celgene.com

  Show 29 Study Locations
Sponsors and Collaborators
Celgene
Investigators
Study Director: Amine Bensmaine, MD Celgene Corporation

Responsible Party: Celgene
ClinicalTrials.gov Identifier: NCT02773030     History of Changes
Other Study ID Numbers: CC-220-MM-001
First Posted: May 16, 2016    Key Record Dates
Last Update Posted: December 3, 2018
Last Verified: November 2018

Keywords provided by Celgene:
Multiple Myeloma
Relapsed
Refractory
Pharmacokinetics
Safety
Efficacy
CC-220
Relapsed and refractory multiple myeloma
Dexamethasone
Daratumumab
Bortezomib

Additional relevant MeSH terms:
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 acetate
Dexamethasone
Daratumumab
Bortezomib
BB 1101
Antibodies, Monoclonal
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal