| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Haematological malignancy |
|
| E.1.1.1 | Medical condition in easily understood language |
| Haematological malignancy |
|
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10066476 |
| E.1.2 | Term | Haematological malignancy |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
-Phase 1: To determine the maximum tolerated dose (MTD)/maximum administered dose (MAD) of SAR650984 (Isatuximab).
-Phase 2 (stage 1): To evaluate the activity of single-agent Isatuximab at different doses/schedules and to select dose and regimen to further evaluate the overall response rate (ORR) of Isatuximab as single agent or in combination with dexamethasone.
-Phase 2 (stage 2): To evaluate the activity in terms of overall response rate (ORR) of Isatuximab at the selected dose/schedule from stage1, as single agent (ISA arm) and in combination with dexamethasone (ISAdex arm). |
|
| E.2.2 | Secondary objectives of the trial |
Phase 1
- To characterize the global safety profile including cumulative toxicities
- To evaluate the pharmacokinetic (PK) profile of isatuximab in the proposed dosing schedule(s)
- To assess the pharmacodynamics (PD), immune response, and preliminary
disease response
Phase 2 (stage 1) : to evaluate the followings objectives for Isatuximab as single
agent:
- Safety
- Efficacy as measured by duration of response, clinical benefit rate, progression free survival, overall survival
Phase 2 (stage 2) : to evaluate the followings objectives in each arm (ISA and
ISAdex):
- Safety
- Efficacy as measured by duration of response, clinical benefit rate, progression free survival, overall survival
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Phase 1:
-For dose escalation cohorts, patients with confirmed selected CD38+ haematological malignancies as specified below who have progressed on after standard therapy or for whom there is no effective standard therapy (refractory/relapsed patients). B-cell Non-Hodgkin-lymphoma/leukemia (NHL) patients having at least 1 measurable lesion. Multiple myeloma (MM) patients with measurable M-protein serum and/or 24-hour urine. Acute myeloid leukemia (AML) patients, all types except M3 based on French-American-British (FAB) classification. Acute lymphoblastic leukemia (B-cell ALL) patients. Chronic lymphocytic leukemia (CLL) patients.
-For expansion cohorts, patients with relapsed/refractory MM with measurable M-protein (serum M-protein of >0.5 g/dL and/or urine M-protein of >200 mg [24-hr urine] or elevated serum free light chains [FLC] >10 mg/dL with abnormal FLC ratio) who have progressed on or after standard therapy that includes an IMiD and a proteasome inhibitor and who meet the protocol defined criteria for standard risk or high risk.
Phase 2:
-Patients must have a known diagnosis of multiple myeloma with evidence of measurable disease, and have evidence of disease progression based on International Myeloma Working Group (IMWG) criteria: Serum M-protein ≥1 g/dL (≥0.5 g/dL in case of IgA disease for stage 2), or urine M-protein ≥200 mg/24 hours or in the absence of measurable m-protein, serum FLC ≥10 mg/dL, and abnormal serum immunoglobulin kappa lambda FLC ratio (<0.26 or >1.65).
-Patients must have received at least three prior lines of therapy for MM and must include treatment with an Immunomodulatory drug (IMiD) (for ≥2 cycles or
≥2 months of treatment) and a proteasome inhibitor (PI) (for ≥2 cycles or
≥2 months of treatment) or patients whose disease is double refractory to an IMiD and a PI. For patients who have received more than 1 type of IMiD and PI, their disease must be refractory to the most recent one.
-Patients must have achieved a minimal response or better to at least one prior line of therapy.
-Patients must have received an alkylating agent (≥2 cycles or ≥2 months) either alone or in combination with other MM treatments.
-Stage 2 only : Patients must have evidence of disease progression on or after
the most recent prior regimen based on IMWG criteria. |
|
| E.4 | Principal exclusion criteria |
Phase 1:
- Karnofsky performance status <60.
- Poor bone marrow reserve.
- Poor organ function.
-Known intolerance to infused protein products, sucrose, histidine, polysorbate 80 or known hypersensitivity to any of the components of the study therapy that is not amenable to pre-medication with steroids and H2 blockers.
-Any serious active disease (including clinically significant infection that is chronic, recurrent, or active) or co-morbid condition, which, in the opinion of the investigator, could interfere with the safety, the compliance with the study or with the interpretation of the results.
-Any severe underlying medical conditions including presence of laboratory abnormalities, which could impair the ability to participate in the study or the interpretation of its results.
Phase 2:
-Patients with multiple myeloma immunoglobulin M (IgM) subtype.
-Previous treatment with any anti-CD38 therapy.
-Patients with concurrent plasma cell leukemia.
-Patients with known or suspected amyloidosis.
-Karnofsky performance status <60 (stage 1)/ECOG Performance status >2 (stage 2)
-Poor bone marrow reserve.
-Poor organ function.
-Known intolerance to infused protein products, sucrose, histidine, polysorbate
80 or known hypersensitivity to any of the components of the study therapy that
is not amenable to pre-medication with steroids and H2 blockers.
-Any serious active disease (including clinically significant infection that is
chronic, recurrent, or active) or co-morbid condition, which, in the opinion of the
investigator, could interfere with the safety, the compliance with the study or with
the interpretation of the results.
-Any severe underlying medical conditions including presence of laboratory
abnormalities, which could impair the ability to participate in the study or the
interpretation of its results. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Dose Limtiting Toxicities (DLTs)
Overall Response Rate
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Dose Limtiting Toxicities (DLTs) : 4 weeks
Overall Response Rate : 4 months |
|
| E.5.2 | Secondary end point(s) |
1 - Safety as assessed from adverse events reporting, laboratory tests, vital signs according to the National Cancer Institute - Common Toxicity Criteria (NCI-CTC) version 4.0 grade scaling.
2 - Main PK parameters: Area under the serum concentration time curve (AUC), maximum observed concentration (Cmax), Time to reach Cmax (tmax)
3 - Main PD Biomarker: CD38 receptor occupancy and receptor density
4 - Immune response: levels of human anti-human antibodies
5 - Duration of Response
6 - Patient reported outcomes
7 - Overall Survival
8 - Clinical Benefit Rate
9 - Progression Free Survival |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1 - Up to end of treatment + 30 days, up to a maximum study duration of 36 months
2 - up to end of treatment + 60 days
3 - Up to end of treatment
4 - Up to end of treatment + 60 days
5 - 12 months from last patient in
6 - every 4 weeks up to end of treatment
7 - 8 - 9 - 12 months from last patient in |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | Yes |
| 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 | Yes |
| 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 | 2 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| 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 |
| Argentina |
| Brazil |
| Chile |
| Israel |
| Mexico |
| Peru |
| United States |
| Austria |
| Finland |
| Spain |
| Greece |
| Italy |
| Belgium |
| Russian Federation |
| Turkey |
| Ukraine |
| United Kingdom |
|
| 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
|
| Last visit of the last subject |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 13 |
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