Purpose

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

Eligibility

Eligible Ages
Over 18 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

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

Study Design

Phase
Phase 1/Phase 2
Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel Assignment
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
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 names:
    • 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 names:
    • 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 names:
    • 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 names:
    • 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 names:
    • 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 names:
    • Velcade

Recruiting Locations

Mayo Clinic
Scottsdale, Arizona 85259

University of Arkansas for Medical Sciences
Little Rock, Arkansas 72205

Winship Cancer Institute of Emory University
Atlanta, Georgia 30322

University of Maryland School of Med
Baltimore, Maryland 21201

University of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan 48109

Karmanos Cancer Institute
Detroit, Michigan 48201

Hackensack University Medical Center
Hackensack, New Jersey 07601

Icahn School of Medicine at Mount Sinai Medical Center
New York, New York 10029

More Details

NCT ID
NCT02773030
Status
Recruiting
Sponsor
Celgene

Study Contact

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

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.

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.