A randomized phase III trial assessing the benefit of the addition of isatuximab to lenalidomide / bortezomib / dexamethasone (RVd) induction and lenalidomide maintenance in patients with newly diagnosed multiple myeloma (GMMG-HD7)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universitaetsklinikum Heidelberg AöR

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

18 Oct 2018 → ongoing

Decision date (initial)

2024-07-31

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Bristol Myers Squibb (Celgene) · Sanofi-Aventis Deutschland GmbH

External identifiers

EU CT number

2024-513464-26-00

EudraCT number

2017-004768-37

ClinicalTrials.gov

NCT03617731

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Efficacy

The two primary objectives are:
(1) to compare the induction regimen (IA vs IB) regarding minimal residual disease (MRD) negativity after induction (assessed by flow cytometry; sensitivity 1e-5), and (2) to compare the maintenance strategies (arms IIA vs IIB) regarding progression-free survival (PFS), defined as time from 2nd randomization (prior to maintenance therapy) to progression or death from any cause whichever occurs first.

Secondary objectives 3

1. To compare the four treatment arms (IA-IIA, IA-IIB, IB-IIA, IB-IIB) regarding progression-free survival (PFS), defined as time from 1st randomization (at study inclusion) to progression or death from any cause, whichever occurs first
2. To assess the treatment effect of the induction phase regarding PFS from 1st randomization. Induction treatment effect will be assessed by comparing a) the overall IA to IB (independently on 2nd randomization) and additionally by comparing the treatment arms IA-IIA to IB-IIA (induction treatment followed by lenalidomide maintenance)
3. To compare the treatment arms regarding: - Overall survival (OS) from 1st randomization (all four treatment arms and induction treatment arms IA to IB and IA-IIA versa IB-IIA) and from 2nd randomization (maintenance treatment arms IIA vs IIB)7 - Complete response (CR) rates after induction therapy, high dose therapy, and during/after maintenance therapy (CR as defined by IMWG) adjusted after removal of isatuximab interference in the immunofixation test in the relevant patient subpopulations - MRD negativity after high dose therapy, during and after 3 years of maintenance treatment (assessed by flow cytometry) - Sustained MRD negativity for ≥6 months / ≥12 months - Best response to treatment during the trial - PFS 2 (PFS after next line of therapy) from 2nd randomization - Toxicity during induction and maintenance with respect to adverse events of CTC grade ≥ 3 (and specific adverse events of CTC grade ≥ 2 as defined in chapter 11.3) and serious adverse events - Quality of life assessment (using EORTC-QLQC30, EORTC-QLQMY20, and EQ-5D-5L questionnaires) - To characterize the pharmacokinetics of isatuximab in combination with lenalidomide/ bortezomib/ dexamethasone or in combination with lenalidomide/dexamethasone in this population (subgroup of patients, at selected sites)

Conditions and MedDRA coding

Multiple Myeloma

Study design 3 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Patients meeting all of the following criteria will be considered for admission to the trial:
2. Confirmed diagnosis of untreated multiple myeloma requiring systemic therapy.
3. Patient is eligible for high dose therapy and autologous stem cell transplantation.
4. Measurable disease, defined as any quantifiable monoclonal protein value, defined by at least one of the following three measurements:34 • Serum M-protein ≥ 10g/l (for IgA ≥ 5g/l) • Urine light-chain (M-protein) of ≥ 200 mg/24 hours • Serum FLC assay: involved sFLC level ≥ 10 mg/dl and abnormal sFLC ratio
5. Age 18 - 70 years inclusive
6. WHO performance status 0-2
7. Negative pregnancy test at inclusion (females of childbearing potential).
8. All patients must agree on the requirements regarding the lenalidomide pregnancy prevention plan described in section 6. For all men and females of childbearing potential: patients must be willing and capable to use adequate contraception during the complete therapy.
9. All patients must • agree to abstain from donating blood while taking lenalidomide and for 28 days following discontinuation of lenalidomide therapy • agree not to share study drug lenalidomide with another person and to return all unused study drug to the investigator or pharmacist
10. Ability of patient to understand character and individual consequences of the clinical trial.
11. Provide written informed consent (must be available before enrolment in the trial).

Exclusion criteria 23

1. Patients presenting with any of the following criteria will not be included in the trial:
2. Patient has known hypersensitivity (or contraindication) to dexamethasone, sucrose histidine (as base and hydrochloride salt), boron, mannitol, and polysorbate 80 or any of the components of study therapy that are not amenable to premedication with steroids or H2 blockers that would prohibit further treatment with these agents.
3. Systemic AL amyloidosis (except for AL amyloidosis of the skin or the bone marrow)
4. Plasma cell leukemia
5. Previous chemotherapy or radiotherapy during the past 5 years except local radiotherapy in case of local myeloma progression or benign diseases, such as nonmalignant thyroid diseases. (Note: patients may have received a cumulative dose of up to 160 mg of dexamethasone or equivalent as emergency therapy.) Previous therapy due to smouldering myeloma may be acceptable. In this case the GMMG study office has to be consulted prior to inclusion.
6. Severe cardiac dysfunction (NYHA classification III-IV), ejection fraction < 40%.
7. Significant hepatic dysfunction (ASAT and/or ALAT ≥ 3 times normal level and/or serum bilirubin ≥ 1.5 times normal level if not due to hereditary abnormalities as Gilbert’s disease), unless related to myeloma.
8. Patients with active or history of hepatitis B or C (Prior hepatitis B may be acceptable if an adequate prophylaxis is being implemented during the course of the study.)
9. HIV positivity
10. Patients with active, uncontrolled infections
11. Patients with severe renal insufficiency (Creatinine Clearance < 30ml/min)
12. Patients with peripheral neuropathy or neuropathic pain, CTC grade 2 or higher (as defined by the NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0)
13. Patients with a history of active malignancy during the past 5 years with the exception of the following malignancies after curative therapy: basal cell carcinoma of the skin, squamous cell skin carcinoma, stage 0 cervical carcinoma or any in situ malignancy (A history of an early stage malignancy during the past 5 years may be acceptable. In this case the GMMG study office has to be consulted prior to study inclusion.)
14. Patients with acute diffuse infiltrative pulmonary and/or pericardial disease
15. Autoimmune hemolytic anemia with positive Coombs test or immune thrombocytopenia
16. Platelet count < 75 x 10^9/l (Platelet transfusions are not permitted to improve platelet count prior to study inclusion.)
17. Haemoglobin ≤ 8.0 g/dl, unless related to myeloma
18. Absolute neutrophil count (ANC) < 1.0 x 10^9/l (the use of colony stimulating factors within 14 days before the test is not allowed)
19. Corrected serum calcium > 14 mg/dl (> 3.5 mmol/l)
20. Unable or unwilling to undergo thromboprophylaxis
21. Pregnancy and lactation
22. Participation in other clinical trials. This does not include long-term follow-up periods without active drug treatment of previous studies during the last 6 months.
23. Prisoners or subjects who are legally institutionalized, or those unwilling or unable to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. The study will investigate two primary endpoints:(1) minimal residual disease (MRD) negativity after induction (assessed by flow cytometry; sensitivity 1e-5), defined as proportion of patients with negative MRD after induction.
2. (2) progression-free survival (PFS), defined as time from 2nd randomization (prior to maintenance) to progression or death from any cause whichever occurs first.

Secondary endpoints 8

1. Key Secondary Endpoint: PFS, defined as time from 1st randomization (at study inclusion) to progression or death from any cause whichever occurs first.
2. OS defined as time from 1st randomization and from 2nd randomization to time of death from any cause. Patients still being alive at the time of the analysis will be censored at the date last known to be alive.
3. Complete response (CR) rates. The analysis will be based on the CR rate which is the proportion of patients achieving complete response (CR) to treatment adjusted after removal of isatuximab interference in the immunofixation test in the relevant patient subpopulations.
4. MRD negativity after high dose therapy, during and after 3 years of maintenance treatment (flow cytometry) defined as the proportion of patients with negative MRD after high dose therapy, during and after 3 years of maintenance treatment (flow cytometry), respectively.
5. Sustained MRD-negativity, defined as the maintenance of MRD-negativity (assessed by NGF at a sensitivity of 10-5) >=6 / >=12 months apart (after first occurrence of MRD negativity)
6. best response to treatment during the trial (adjusted after removal of isatuximab interference in the immunofixation test in the relevant patient subpopulations).
7. PFS 2 (PFS after next line of therapy) from 2nd randomization
8. quality of life

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 5

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitaetsklinikum Heidelberg AöR

Sponsor organisation

Universitaetsklinikum Heidelberg AöR

Address

Im Neuenheimer Feld 672, Neuenheim Neuenheim

City

Heidelberg

Postcode

69120

Country

Germany

Scientific contact point

Organisation

Universitaetsklinikum Heidelberg AöR

Contact name

GMMG Studiensekretariat

Public contact point

Organisation

Universitaetsklinikum Heidelberg AöR

Contact name

GMMG Studiensekretariat

Locations

1 EU/EEA country · 67 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 13 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications