| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed and refractory multiple myeloma (RRMM) |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10028229 |
| E.1.2 | Term | Multiple myelomas |
| E.1.2 | System Organ Class | 100000004851 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10067095 |
| E.1.2 | Term | Multiple myeloma progression |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Part 1:
- To assess the pharmacokinetics (PK), safety/tolerability and define the maximally tolerated dose (MTD)/recommended Phase 2 dose (RP2D) of CC-92480 in combination with dexamethasone in conjunction with a minimum of two CC- 92480 dosing schedules.
- To assess the PK, safety/tolerability and define the MTD/RP2D of CC-92480 monotherapy on the QD 21/28 dosing schedule.
Part 2:
- To determine the efficacy of CC-92480 in combination with dexamethasone in subjects with RRMM in cohort expansion, as measured by overall response rate (ORR). |
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| E.2.2 | Secondary objectives of the trial |
- To assess the safety/tolerability of CC-92480 in combination with dexamethasone in subjects with RRMM in cohort expansion.
- To evaluate additional efficacy parameters of CC-92480 in combination with dexamethasone in subjects with RRMM in cohort expansion including time-to-response (TTR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS).
- To assess the preliminary efficacy of CC-92480 in combination with dexamethasone in subjects in Part 1.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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. Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2.
5. Subjects must have a documented diagnosis of MM and measurable disease at enrollment. Measurable disease is defined as:
a. M-protein quantities ≥ 0.5 g/dL by sPEP or
b. ≥ 200 mg/24 hour urine collection by uPEP or
c. Serum FLC levels > 100 mg/L (milligrams/liter) involved light chain and an abnormal kappa/lambda (κ/λ) ratio in subjects without measurable or urine M-protein or
d. for subjects with immunoglobulin class A (IgA) myeloma whose disease can only be reliably measured by quantitative immunoglobulin measurement, a serum IgA level ≥ 0.50 g/dL
6. All subjects must have:
a. received at least 3 prior anti-myeloma regimens including at least 2 consecutive cycles of lenalidomide, pomalidomide, a proteasome inhibitor, a glucocorticoid and a CD38 antibody (note: induction with or without bone marrow transplant and with or without maintenance therapy is considered one regimen),
b. documented disease progression on or within 60 days from the last dose of their last myeloma therapy,
i. subjects who had CAR-T therapy as their last myeloma therapy are eligible as long as they have documented disease progression following CAR-T therapy,
c. in addition to criteria above (a and b), subjects enrolled in Part 2, must have disease refractory to an immunomodulatory agent (lenalidomide and/or pomalidomide), a glucocorticoid, a proteasome inhibitor, and a CD38 antibody. Refractory is defined as disease that is nonresponsive on therapy (failure to achieve minimal response or development of progressive disease), or progresses within 60 days of last dose.
7. Subjects must have the following laboratory values:
a. Absolute neutrophil count (ANC) ≥ 1.25 x 10 to the power of 9 /L without growth factor support for ≥ 7 days (≥ 14 days for pegfilgrastim). ANC of ≥ 1.00 x 10 to the power 9/L is permitted for the dose expansion cohorts (Part 2).
b. Hemoglobin (Hgb) ≥ 8 g/dL.
c. Platelets (plt) ≥ 75 x 10 to the power of 9 /L without transfusion for ≥ 7 days (≥ 50 x 10 to the power of 9 /L for subjects with > 50% plasma cells in bone marrow).
d. Corrected serum calcium ≤ 13.5 mg/dL (≤ 3.4 mmol/L).
e. Creatinine clearance (CrCl) based on Cockcroft-Gault formula ≥ 45 mL/min.
f. AST/SGOT and ALT/SGPT ≤ 3.0 x upper limit of normal (ULN).
g. Serum bilirubin ≤ 1.5 x ULN or < 3.0 mg/dL for subjects with documented Gilbert’s syndrome.
h. Uric acid ≤ 7.5 mg/dL (446 µmol/L).
i. PT/INR < 1.5 x ULN and partial thromboplastin time (PTT) < 1.5 x ULN, (for subjects not receiving therapeutic anticoagulation).
8. Females of childbearing potential (FCBP) must:
a. Have two negative pregnancy tests as verified by the Investigator prior to starting study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after discontinuation of CC-92480. This applies even if the subject practices true abstinence from heterosexual contact.
b. 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 reliable forms of contraception as defined in the PPP (Appendix 4) and provided to the subject at the time of informed consent, without interruption, 28 days prior to starting CC-92480, during the study therapy (including during dose interruptions), and for 28 days after discontinuation of study therapy.
1. Male subjects must:
Practice true abstinence (which must be reviewed on a monthly basis and source documented) or agree to use of a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study (even during dose interruptions) and for at least 3 months following CC-92480 discontinuation in accordance with the PPP (Appendix 4) provided to the subject at the time of informed consent, 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 coitus interruptus (withdrawal) are not acceptable methods of contraception.
2. Males must agree to refrain from donating sperm while on CC-92480 for 90 days after its discontinuation. Females must agree to refrain from donating ova while on CC-92480 for 28 days after its discontinuation.
3. All subjects must agree to refrain from donating blood while on CC-92480 and for 28 days after its discontinuation. |
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| E.4 | Principal exclusion criteria |
The presence of any of the following will exclude a subject from enrollment:
1. Subject has a 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 non-secretory multiple myeloma.
5. Subject has refractory primary multiple myeloma (ie, no history of at least a minor response to a prior treatment regimen).
6. Subject has plasma cell leukemia or active leptomeningeal myelomatosis.
7. Subject has documented, systemic light chain amyloidosis or Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, and Skin changes (POEMS) Syndrome.
8. Subject has immunoglobulin class M (IgM) myeloma.
9. Part 1: Subject has a history of allogeneic bone marrow transplantation. Part 2: Subject has a history of allogeneic bone marrow transplantation within 6 months prior to first dose. Subject should not have ongoing graft-versus-host disease (GVHD) requiring systemic immunosuppression.
10. Subject is undergoing dialysis.
11. Subjects with peripheral neuropathy ≥ Grade 2.
12. Subjects with gastrointestinal disease that may significantly alter the absorption of CC-92480.
13. Subject has impaired cardiac function or clinically significant cardiac disease, including any of the following:
• LVEF < 45% as determined by ECHO or MUGA scan at Screening.
• Complete left bundle branch, bifascicular block or other clinically significant abnormal electrocardiographic (ECG) finding at Screening.
• A prolongation of QT interval on Screening ECG as defined by repeated demonstration of a QTc interval >480 milliseconds (ms) using Fridericia’s QT correction formula; a history of or current risk factors for Torsades de Pointe (eg. heart failure, hypokalemia, or a family history of Long QT Syndrome); and concurrent administration of medications that prolong the QT/QTc interval.
• Congestive heart failure (New York Heart Association Class III or IV).
• Myocardial infarction ≤6 months prior to starting CC-92480.
• Unstable or poorly controlled angina pectoris, including the Prinzmetal variant of angina pectoris.
14. Concurrent administration of strong CYP3A modulators; concurrent administration of proton-pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, pantoprazole) ≤ 2 weeks prior to starting CC-92480 (see Section 8.2).
15. Subject had prior systemic myeloma treatment with an investigational anti-myeloma agent (eg, anti-PD-1, anti-PD-L1) ≤ 5 half-lives prior to starting CC-92480 (not applicable for subjects who had CAR-T as last prior regimen); subject had prior exposure
to approved myeloma therapies (including therapeutic monoclonal antibodies such as anti-CD38 or anti-SLAM-7) ≤ 5 half-lives or within 4 weeks prior to starting CC-92480 whichever is shorter.
16. Subject had major surgery ≤ 2 weeks prior to starting CC-92480. Note: Subjects must have recovered from any clinically significant effects of recent surgery.
17. Subject is a pregnant or nursing female, or intends to become pregnant or donate ova during participation in the study.
18. Subject has known human immunodeficiency virus (HIV) infection.
19. Subject has known active chronic hepatitis B or C virus (HBV/HCV) infection.
20. Subject has a history of concurrent second cancer requiring ongoing systemic treatment.
21. Subjects has a history of prior malignancy other than MM, except if the subject has been free of disease for ≥3 years OR the subject had one of the following noninvasive malignancies treated with curative intent without known recurrence:
a. Basal or squamous cell carcinoma of the skin.
b. Carcinoma in situ of the cervix or breast.
c. Stage 1 bladder cancer.
d. Incidental histological findings of localized prostate cancer such as tumor stage 1a or 1b (T1a or T1b) using the Tumor/Node/Metastasis (TNM) classification of malignant tumors OR prostate cancer that has been treated with curative intent.
22. Subject has a history of anaphylaxis to thalidomide, lenalidomide, pomalidomide or dexamethasone.
23. Subject has known or suspected hypersensitivity to the excipients (excipients include silica dimethyl silylate, anhydrous colloidal silicon dioxide, mannitol, fumaric acid and stearic acid) contained in the formulation of CC-92480 or dexamethasone.
24. Subject has undergone either of the following within 14 days of initiating CC-92480:
a. Plasmapheresis.
b. Radiation therapy other than local therapy for symptomatic relief of MM associated bone lesions.
Please refer to Protocol Amendment 06, dated 10 June 2020 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety:
Type, frequency, seriousness, severity and relationship of AEs to CC-92480 and dexamethasone; changes from baseline in clinically-relevant physical findings, vital signs, selected laboratory analytes, ECGs and ECHO/MUGA scans.
PK parameters:
Area under the plasma concentration-time curve (AUC), maximal plasma concentration (Cmax), time to Cmax (Tmax), terminal-phase elimination half-life (t1/2), apparent total clearance of the drug from plasma after oral administration (CL/F) and apparent volume of distribution during terminal phase after non-intravenous administration (Vz/F) for CC-92480 monotherapy and in combination with dexamethasone and the R- enantiomer (CC0982796) of CC-92480 (if data allow).
Recommended Phase 2 Dose:
Establish the MTD/RP2D for CC-92480 monotherapy and in combination with dexamethasone at each dosing schedule.
Overall Response Rate (ORR)
Best response ≥ partial response (PR), according to the IMWG Uniform Response Criteria. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety:
Part 1: From first subject first visit until 28 days after the last subject discontinues study treatment.
PK Parameters: Part 1, cycle 1.
Recommended Part 2 Dose: Part 1.
ORR: Part 2: From first subject dose of IP until the last subject is no longer evaluable for response or has progressed. |
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| E.5.2 | Secondary end point(s) |
Overall response rate (ORR):
Best response ≥ PR, according to the IMWG Uniform Response Criteria.
Safety:
Type, frequency, seriousness, severity and relationship of AEs to CC-92480 and dexamethasone; changes from baseline in clinically-relevant physical findings, vital signs, selected laboratory analytes, ECGs and ECHO/MUGA scans.
Time to response (TTR):
Time from 1st dose of CC-92480 to the first documentation of response ≥ PR.
Duration of response (DOR):
Time from the first documentation of response ( ≥ PR) to the first documentation of PD or death.
Progression free survival:
Time from 1st dose of CC-92480 to the first occurrence of disease progression or death from any cause.
Overall survival (OS):
Time from first dose of CC-92480 to death due to any cause
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
ORR:
From first subject dose of IP until the last subject is no longer evaluable for response or has progressed.
Safety:
Part 2: From first subject first visit until 28 days after the last subject discontinues study treatment.
TTR:
From first subject dose of IP until the last subject is no longer evaluable for response or has progressed.
DOR:
From first subject dose of IP until the last responder is no longer evaluable for response or has progressed.
Progression free survival:
From first subject dose of IP until the last subject discontinues study participation.
OS:
From first subject dose of IP until the last subject discontinues study.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 26 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Belgium |
| Canada |
| Denmark |
| Finland |
| Greece |
| Japan |
| Korea, Republic of |
| Spain |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The End of Trial is defined as either the date of the last visit of the last subject to complete the 5-year long-term follow-up from the date of the last subject enrolled in Part 2, or the date of receipt of the last data point from the last subject that is required for primary, secondary and/or exploratory analysis, as specified herein, whichever is the later date. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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