| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Newly diagnosed multiple myeloma |
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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 | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028228 |
| E.1.2 | Term | Multiple myeloma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy (rate of improvement in response from PR to ≥ VGPR; from VGPR to ≥CR; from CR to sCR) of three different dose levels of Iberdomide in maintenance treatment after ASCT |
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| E.2.2 | Secondary objectives of the trial |
To determine:
1.Rate of NGF MRD conversion from positive to negative
2.Rate of adverse events
3.Safety and efficacy in different subset of subjects with different prognostic features
4.Time to Progression (TTP)
5.Progression Free Survival (PFS)
6.Time to next therapy (TNT)
7.Progression Free Survival 2 (PFS2)
8.Overall survival (OS)
9.Pharmacokinetics (PK) of iberdomide |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
1. Immune monitoring by flow cytometry
Evaluation of immune-status during therapy with Iberdomide maintenance by means of assessment of cellular subsets (T cells, NK cells, B cells, NK T cells, and immune suppressor cells including Tregs, Bregs, and MDSCs) in longitudinally obtained blood and bone marrow samples (both collected at entry, C2D15 – blood only, after 6 and 12 months of Iberdomide treatment and at the time of progression); Determine T-cell differentiation subsets, the activation status of immune cells, and evaluate expression of immune check points such as PD-1, CTLA-4, LAG-3, and TIM-3 on these immune cells, and analyze expression of several immune-regulatory proteins on MM cells (PD-L1, CD47, HVEM and Gal9). Immune cell subset frequencies and expression levels of proteins will be related to outcome with iberdomide maintenance (response, PFS and OS).
Analysis of the immune profile in blood and bone marrow at the time of relapse.
Changes in the immune-status will also be correlated with response and survival In addition compare immune profile at the time of relapse with the immune profile at baseline to gain a better understanding of mechanisms of resistance.
Differential changes in immune profile between cohorts may be helpful in selecting the optimal dose of iberdomide for further evaluation in a phase 3 study with iberdomide maintenance.
Also a comparative analysis with immune monitoring data obtained in the dose-escalation study with iberdomide will be done (CC-220-MM- 001).
2. Monitoring immune competence at the single cell level:
Single cell RNA sequencing will be used to longitudinally follow up the bone marrow stromal cells and immune cells from patients on Iberdomide-based therapy to chart the response of the micro- environment to Iberdomide at single cell resolution.
Patients will be monitored in a sequential manner (entry, 6 months, 12 months, progression) to compare the inflammatory bone marrow environment in patients that remain MRD negative under Iberdomide treatment vs patients that fail to sustain MRD negativity and progress under treatment. Viably frozen cells will be collected and retrospectively 10 patients in each group will be selected to analyze the inflammatory environment sequentially at 4 time points. For the experiments proposed patients that have reached MRD negativity at the first timepoint during Iberdomide treatment will be selected.
The goal of these experiments will be to determine alterations in the inflammatory stromal cell profiles related to sustained MRD-negativity during Iberdomide treatment, and relate this to bone marrow immune competence as determined by MDSC presence, CD8 T cell exhaustion and immune cell transcriptome.
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| E.3 | Principal inclusion criteria |
Subjects with newly diagnosed MM, requiring therapy due to the presence of CRAB symptoms or myeloma defining events and measurable disease (sPEP >0.5 g/dL and/or uPEP > 200 mg/24h and/or FLC involved > 10 mg/dL with abnormal FLC ratio) before induction therapy with a PI and IMID-containing regimen-; Subjects with complete baseline evaluation at the time of diagnosis according to revised International Staging System (R-ISS) (cytogenetic profile, ISS and LDH); Subjects treated with proteasome inhibitor plus immunomodulatory drug-based induction (3-6 cycles), followed by single or double autologous stem cell transplant (ASCT) with melphalan as condItioning regimen +/- consolidation.; Subjects within 12 months from diagnosis and 120 days after last ASCT, who achieved at least a partial response (PR) after ASCT, according to IMWG criteria; Subjects willing and able to follow the trial procedures; Subjects must understand and voluntary sign an ICF prior to any study related assessment/procedurs being conducted; Age ≥18 years; ECOG performance status 0-1; 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 (i.e., has had menses at any time in the preceding 24 consecutive months) and must:
a. 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.
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 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. Contraception requirements are detailed in Appendix H.; 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.]; 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.; 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 study treatment; All male and female subjects must follow all requirements defined in the Pregnancy Prevention Program (v5.1). See Appendix I for CC-220 Pregnancy Prevention Plan for Subjects in Clinical Trials;
Subject agree to refrain from donating blood while on iberdomide, during dose interruption and for at least 28 days following the last iberdomide dose;
Baseline values:
ANC ≥1.0 x 109/L without use of growth factors;
PLTs≥75 x109/L (transfusions within 14 days from Day1 cycle 1 to achieve this cut off are not allowed);
Hb >8 g/dL (transfusions within 14 days from Day1 cycle 1 to achieve this cut off are not allowed);
Life expectancy ≥ 3 months |
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| E.4 | Principal exclusion criteria |
Systemic AL amyloidosis or plasma cell leukemia (>2.0x109/L circulating plasma cells by standard differential) or Waldenstrom’s macroglobulinemia; Subject has known meningeal involvement of multiple myeloma; History of active malignancy during the past 5 years, except squamous cell and basal cell carcinomas of the skin and carcinoma in situ of the cervix or breast and incidental histologic finding of prostate cancer (T1a or T1b using the TNM [tumor, nodes, metastasis] clinical staging system) or prostate cancer that is cured, or malignancy that in the opinion of the local investigator, with concurrence with the principal investigator, is considered cured with minimal risk of recurrence within 3 years.; Subject with any one of the following: clinically significant abnormal electrocardiogram (ECG) findings at screening; congestive heart failure (New York Heart Association Class III or IV); myocardial infarction within 12 months prior to starting iberdomide; unstable or poorly controlled angina pectoris, including Prinzmetal variant; clinically significant pericardial disease; Peripheral neuropathy of ≥grade 2.; Subject has any concurrent severe and/or uncontrolled medical condition or psychiatric disease 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 or that confounds the ability to interpret data from the study.; Subjects with gastrointestinal disease that may significantly alter the absorption of iberdomide; Subject with known history of anaphylaxis or hypersensitivity to thalidomide, lenalidomide, pomalidomide; Subject with known or suspected hypersensitivity to excipients contained in the formulation of iberdomide; Subjects has current or prior use of immunosuppressive medication within 14 days prior to starting therapy with iberdomide (exceptions are intranasal, inhaled, topical or local steroids injections; systemic corticosteroids at doses not exceeding 10 mg/day of prednisone or equivalent; steroids as premedication for hypersensitivity reactions); Subject has taken a strong inhibitor or inducer of CYP3A4/5 including grapefruit, St John’s wort or related products within 2 weeks prior to dosing and during the course of study; Subject known to test positive for HIV or have active hepatitis A, B or C; Subjects is unable or unwilling to undergo protocol required thromboembolism prophylaxis ; Subject is a female who is pregnant nursing or breastfeeding or who intends to become pregnant during the participation; Baseline lab values:
- Creatinine clearance ≤30 ml/min.
- Significant hepatic dysfunction (total bilirubin > 1.5x ULN or AST/ALT > 2.5x ULN), or > 3.0 mg/dL for subjects with documented Gilbert’s syndrome unless related to myeloma
- Corrected serum calcium>13.5 mg/dL (3.4 mmol/L); Any clinical condition at screening that would preclude subject from completing the study |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
"Response improvement rate within 6 months will be measured as the number of subjects that improve response according to IMWG criteria (from PR to ≥VGPR; from VGPR to ≥CR; from CR to >sCR) within the end of sixth cycle of treatment.
Dose reductions/discontinuation rate within 6 months will be measured as the number of subjects that discontinued treatment or have a dose modification within the end of sixth cycle of treatment. "
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
6 months (after the end of 6 treatment cycles)
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| E.5.2 | Secondary end point(s) |
TTP will be measured by protocol from the date of start of therapy and according to ITT from the date of eligibility confirmation to the date of first observation of PD, or deaths for PD. Subjects who have not progressed or who withdraw from the study or die from causes other than PD will be censored at the time of the last disease assessment. Subjects lost to FU will also be censored at the time of last complete disease assessment.
PFS will be measured by protocol from the date of start of therapy and according to ITT from the date of eligibility confirmation to the date of first observation of PD, or death from any cause as an event. Subjects who have not progressed or who withdraw from the study or who were lost to FU will be censored at the time of the last disease assessment.
TNT will be measured by protocol from the date of start of therapy and according to ITT from the date of eligibility confirmation to the date of next anti-myeloma therapy. Death due to any cause before starting therapy will be considered an event. Subjects who have not progressed or who withdraw from the study will be censored at the time of the last disease assessment. Subjects lost to FU will also be censored at the time of last contact.
PFS2 will be measured by protocol from the date of start of therapy and according to ITT from the date of eligibility confirmationto the date of observation of second disease progression (i.e. progression after the second line of therapy) or death to any cause as an event. In case of date of second progression is not available, date of start of third line treatment can be used. Subjects who have not progressed or who withdraw from the study will be censored at the time of the last complete disease assessment. All subjects who were lost to follow-up prior to the end of the study, have not progressed, and are still alive will also be censored at the time of last contact.
OS is defined by protocol from the date of start of therapy and according to ITT from the date of eligibility confirmation to the date of death, regardless cause of death. Subjects who withdraw consent will be censored at the time of withdrawal. Subjects who are still alive at the cut-off date of final analysis will be censored at the date of last contact. Subjects lost to FU will also be censored at the time of last contact.
Response rate (sCR, CR, VGPR) will be evaluated according to IMWG Response criteria
Rate of NGF Minimal residual disease (MRD) conversion from positive to negative
The MRD conversion rate at 6 months is determined as the proportion of subjects with MRD negativity (≥10-5 sensitivity level, by NGF) after 6 months converted from status as Positive at screening.
The MRD conversion rate at 12 months is determined as the proportion of subjects with MRD negativity (≥10-5 sensitivity level, by NGF) after 12 months converted from status as Positive at screening. Subjects who withdraw from the study or are lost to follow up before post 12 months MRD evaluation, the best MRD assessment will be considered.
The best MRD conversion rate within 12 months is determined as the proportion of subjects with MRD negativity (≥10-5 sensitivity level, by NGF) within 12 months converted from status as Positive at screening. The best MRD assessment will be considered. Subjects who withdraw from the study or are lost to follow up before MRD evaluation, the best MRD assessment will be considered.
The analysis of safety as defined by type, frequency and severity will be done primarily by tabulation of the incidence of AEs as defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. In the by-subject analysis, a subject having the same event more than once will be counted only once. AEs will be summarized by worst CTCAE grade
Dose reduction will be done primarily by tabulation of the incidence of subject with at least one dose reduction and causes.
Relative dose will be evaluated consider the ratio between the administered and the planned dose.
Time to discontinuation for toxicity will be measured from the date of first dose of study drugs to the date of discontinuation due to AE or Death for AE/SPM. Subjects who discontinued drugs due to PD, or death for cause other than AE/SPM will be considered a competing event. Subjects has not discontinued and are still alive and on treatment at the cut-off date of final analysis will be censored at the cut-off date. All subjects who were lost to FU will also be censored at the time of last contact.
Quality of life defined by EORTC QLQ-C30.
Determine whether tumor response and outcome (PFS, PFS2, TTP, TNT and OS) may change in subgroups with different prognosis according to current prognostic factors. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| For the entire duration of the 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
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| 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 | 3 |
| 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 | 7 |
| 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 | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
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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 | 7 |
| 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 | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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