Exploratory study evaluating the relevance of [68Ga]Ga-PentixaFor for initial staging and detection of minimal residual disease in multiple myeloma patients eligible for autologous stem cell transplantation less than 66 years included in the prospective IFM 2020-02.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Universitaire De Nantes

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Diagnosis [E01]

Trial duration

completed 23 May 2023

Decision date (initial)

2022-12-14

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2022-500339-35-01

ClinicalTrials.gov

NCT05321862

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Diagnosis

To determine the sensitivity of [68Ga]Ga-PentixaFor-PET to detect Multiple Myeloma lesions [Bone marrow (BM) lesions and/or extra-medullary disease (EMD)] at the time of initial diagnosis in high risk MM patients included in the MIDAS study.

Secondary objectives 11

1. The specificity, positive predictive value (PPV) and negative predictive value (NPV) of [68Ga]Ga-PentixaFor-PET at the time of initial diagnosis
2. The prognostic impact of FDG-PET and of [68Ga]Ga-PentixaFor-PET depending on the positivity, number and intensity of uptake detected by each imaging technique at the time of initial diagnosis
3. The discrepancies rate between FDG-PET and [68Ga]Ga-PentixaFor-PET at the time of initial diagnosis
4. The clinical and biological factors associated with discrepancies between FDG-PET and [68Ga]Ga-PentixaFor-PET at the time of initial diagnosis
5. The correlation between FDG-PET and [68Ga]Ga-PentixaFor-PET uptakes evaluated by SUV and the RNAseq data evaluated on the myelogram at the time of initial diagnosis
6. Tolerance of [68Ga]Ga-PentixaFor-PET at the time of initial diagnosis
7. The discrepancies rate between FDG-PET and [68Ga]Ga-PentixaFor-PET after induction therapy
8. The prognostic impact of FDG-PET and [68Ga]Ga-PentixaFor-PET depending on the positivity, number and intensity of uptake detected by each imaging technique after induction therapy
9. The link between FDG-PET and [68Ga]Ga-PentixaFor-PET results and minimal residual disease evaluated by NGS after induction therapy
10. Tolerance of [68Ga]Ga-PentixaFor-PET after induction therapy
11. To identify a MM-specific SUV cut off value to discriminate between PTF positive and negative lesions.

Conditions and MedDRA coding

Multiple Myeloma

Study design 1 period

Regulatory references

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Male or female subjects, 18 years of age or older, younger than 66 years (< 66 years)
2. Voluntary written informed consent must be given before performance of any study-related procedure not part of normal medical care, with the understanding that the subject may withdraw consent at any time without prejudice to future medical care
3. Subject must have documented symptomatic multiple myeloma satisfying the CRAB and/or SLIM criteria and measurable disease as defined by: • Monoclonal plasma cells in the bone marrow ≥ 10% or presence of a biopsy proven plasmacytoma AND any one or more of the following myeloma defining events: - Hypercalcemia: serum calcium > 0.25 mmol/L (> 1 mg/dL) higher than ULN or > 2.75 mmol/L (> 11 mg/dL) - Renal insufficiency: creatinine clearance < 40mL/min or serum creatinine > 177 μmol/L (> 2 mg/dL) - Anemia: hemoglobin > 2 g/dL below the lower limit of normal or hemoglobin < 10 g/dL - Bone lesions: one or more osteolytic lesions on skeletal radiography, CT or PET-CT - Clonal bone marrow plasma cell percentage ≥ 60% - Involved: uninvolved serum free light chain ratio ≥ 100 - More than 1 focal lesion on MRI studies • Measurable disease as defined by the following: Serum M-component ≥ 5g/L, and/or urine M-component ≥ 200 mg/24h and/or serum FLC ≥ 100 mg/L
4. Newly diagnosed subjects eligible for high dose therapy and autologous stem cell transplantation
5. Eastern Cooperative Oncology group performance status (ECOG score) ≤ 2(Karnofsky performance status score ≥ 50% =)
6. Subject must have pretreatment clinical laboratory values meeting the following criteria during the Screening Phase (Lab tests should be repeated if done more than 15 days before C1D1): a- Hemoglobin ≥ 7.5 g/dL (≥ 5mmol/L). Prior red blood cell [RBC] transfusion or recombinant human erythropoietin use is permitted; b- Absolute neutrophil count (ANC) ≥ 1.0 Giga/L (GCSF use is permitted); c- ASAT ≤ 3 x ULN; d- ALAT ≤ 3 x ULN; e- Total bilirubin ≤ 3 x ULN (except in subjects with congenital bilirubinemia, such as Gilbert syndrome, direct bilirubin ≤ 1.5 x ULN); f- Calculated creatinine clearance ≥ 40 mL/min/1.73 m²; g- Albumin corrected serum calcium ≤ 14 mg/dL (< 3.5 mmol/L); or free ionized calcium ≤6.5 mg/dL (≤ 1.6 mmol/L); h- Platelet count ≥ 50 Giga/L for subjects in whom < 50% of bone marrow nucleated cells are plasma cells; otherwise platelet count > 30 Giga/L (platelets transfusions performed less than 15 days before C1D1 are not permitted).
7. Women of childbearing potential must have a negative serum or urine pregnancy test 10 to 14 days prior to therapy and repeated within 24 hours before starting study drug. They must commit to continued abstinence from heterosexual intercourse or begin 2 acceptable methods of birth control (One highly effective method and one additional effective method) used at the same time, beginning at least 4 weeks before initiation of Lenalidomide treatment and continuing for at least 90 days after the last dose of Lenalidomide, Iberdomide and 5 months after last dose of Isatuximab. Women must also agree to notify pregnancy during the study.
8. Men must agree to not father a child and agree to use a latex condom during therapy and during dose interruptions and for at least 90 days after the last dose of study drug including Lenalidomide and Iberdomide and 5 months after last dose of Isatuximab, even if they have had a successful vasectomy, if their partner is of childbearing potential. Patient must also refrain from donating sperm during this period.

Exclusion criteria 29

1. Subjects must not have been treated previously with any systemic therapy for multiple myeloma. Prior treatment with corticosteroids or radiation therapy does not disqualify the subject (the maximum dose of corticosteroids should not exceed the equivalent of 160 mg of dexamethasone in a 2-week period). Two weeks must have elapsed since the date of the last radiotherapy treatment. Enrolment of subjects who require concurrent radiotherapy (which must be localized in its field size) should be deferred until the radiotherapy is completed and 2 weeks have elapsed since the last date of therapy
2. Subject with a current diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, or solitary plasmacytoma.
3. Subject has a diagnosis of Waldenström’s macroglobulinemia, or other conditions in which IgM M-protein is present in the absence of a clonal plasma cell infiltration with lytic bone lesions
4. Subject has had plasmapheresis within 14 days of C1D1
5. Subject is exhibiting clinical signs of meningeal involvement of multiple myeloma
6. Myocardial infarction within 4 months prior to enrolment according to NYHA Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities
7. Uncontrolled hypertension
8. Subjects with a history of moderate or severe persistent asthma within the past 2 years, or with uncontrolled asthma of any classification at the time of screening (Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study
9. Intolerance to hydration due to pre-existing pulmonary or cardiac impairment
10. Subject has plasma cell leukemia (according to WHO criterion: ≥ 20% of cells in the peripheral blood with an absolute plasma cell count of more than 2 × 109/L) or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
11. Any clinically significant, uncontrolled medical conditions that, in the Investigator’s opinion, would expose the patient to excessive risk or may interfere with compliance or interpretation of the study results
12. Systemic treatment with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin), strong inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John’s wort within 14 days before the first dose of study treatment
13. Known intolerance to steroid therapy, mannitol, pregelatinized starch, odium stearyl fumarate, histidine (as base and hydrochloride salt), arginine hydrochloride, poloxamer 188, sucrose or any of the other components of study intervention that are not amenable to premedication with steroids and H2 blockers or would prohibit further treatment with these agents
14. History of allergy to any of the study medications, their analogues, or excipients in the various formulations
15. Subject has had major surgery within 2 weeks before study inclusion (informed consent signature) or will not have fully recovered from surgery, or has surgery planned during the time the subject is expected to participate in the study. Kyphoplasty or Vertebroplasty are not considered major surgery
16. Clinically relevant active infection or serious co-morbid medical conditions
17. Prior malignancy except adequately treated basal cell or squamous cell skin cancer, in situ cervical, breast or prostate cancer free of disease since 5 years
18. Female subject who is pregnant or breast-feeding
19. Serious medical or psychiatric illness likely to interfere with participation in study
20. Uncontrolled diabetes mellitus
21. Known HIV infection; Known active hepatitis A, B or C viral infection
22. Uncontrolled or active HBV infection: Patients with positive HbsAg and/or HBV DNA Of note: • Patient can be eligible if anti-HBc IgG positive (with or without positive anti-HBs) but HbsAg and HBV DNA are negative. o If anti-HBV therapy in relation with prior infection was started before initiation of IMP, the anti-HBV therapy and monitoring should continue throughout the study treatment period. • Patients with negative HbsAg and positive HBV DNA observed during screening period will be evaluated by a specialist for start of anti-viral treatment: study treatment could be proposed if HBV DNA becomes negative and all the other study criteria are still met.
23. Active HCV infection: positive HCV RNA and negative anti-HCV Of note: • Patients with antiviral therapy for HCV started before initiation of IMP and positive HCV antibodies are eligible. The antiviral therapy for HCV should continue throughout the treatment period until seroconversion. • Patients with positive anti-HCV and undetectable HCV RNA without antiviral therapy for HCV are eligible.
24. Active systemic infection and severe infections requiring treatment with a parenteral administration of antibiotics
25. Incidence of gastrointestinal disease that may significantly alter the absorption of oral drugs
26. Subjects unable or unwilling to undergo antithrombotic prophylactic treatment
27. Person under guardianship, trusteeship or deprived of freedom by a judicial or administrative decision
28. Previous or concurrent second malignancy except for adequately treated basal cell carcinoma of the skin, curatively treated in situ carcinoma of the cervix, curatively treated solid cancer, with no evidence of disease for at least 2 years
29. Patient with uncontrolled insulin-dependent or non-insulin-dependent diabetes mellitus

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Sensitivity will be assessed by patient and lesion analysis by defining: • True positive (TP): - positive lesion with [68Ga]Ga-PentixaFor-PET and confirmed by another imaging method (FDG-PET/CT, CT scan or MRI) and follow-up or confirmed by histology. • False negative (FN): - negative lesion with [68Ga]Ga-PentixaFor-PET and positive by FDG-PET and confirmed by CT scan/ MRI or histology, or confirmed by follow-up

Secondary endpoints 10

1. The specificity (PPV and NPV) of [68Ga]Ga-PentixaFor-PET at the time of initial diagnosis will be assessed by patient and lesion analysis using the same definitions of TP and FN as for the primary objective at the time of initial diagnosis
2. The prognostic impact of FDG-PET and [68Ga]Ga-PentixaFor-PET based on the number of lesions detected and their intensity of uptake by each imaging technique will be evaluated by assessing the impact of these data on the PFS and OS at the time of initial diagnosis. PFS is defined as the time from the start of treatment to relapse or progression. OS is defined as the time from the start of first treatment to death
3. We will consider as discordant a lesion positive by FDG-PET but negative by [68Ga]Ga-PentixaFor-PET and/or a lesion negative by FDG-PET but positive by [68Ga]Ga-PentixaFor-PET at the time of initial diagnosis
4. [68Ga]Ga-PentixaFor and FDG uptakes assessed by SUV and the quantitative expression of biological markers on myelogram (including expression of the gene coding for hexokinases) at the time of initial diagnosis
5. Tolerance of [68Ga]Ga-PentixaFor will be assessed by clinical monitoring of the patient for 1 hour after [68Ga]Ga-PentixaFor injection. Clinical data (heart rate, oxygen saturation and blood pressure) will be collected prior and 5/10 min after [68Ga]Ga-PentixaFor injection before acquisition (at 60 min after the injection) and at the end of acquisition (at approximately 80 min after the injection) at the time of initial diagnosis
6. We will consider as discordant a lesion positive by FDG-PET but negative by [68Ga]Ga-PentixaFor-PET and/or a lesion negative by FDG-PET but positive by [68Ga]Ga-PentixaFor-PET after induction therapy
7. The prognostic impact of [68Ga]Ga-PentixaFor-PET after therapy will be determined by evaluating the impact of a decrease uptake and/or a normalization of images on PFS and OS after induction therapy
8. FDG-PET and [68Ga]Ga-PentixaFor-PET results (positive/negative) and minimal residual disease evaluated by NGS (positive/negative) after induction therapy
9. Tolerance of [68Ga]Ga-PentixaFor will be assessed by clinical monitoring of the patient for 1 hour after [68Ga]Ga-PentixaFor injection. Clinical data (heart rate, oxygen saturation and blood pressure) will be collected prior and 5/10 min after [68Ga]Ga-PentixaFor injection before acquisition (at 60 min after the injection) and at the end of acquisition (at approximately 80 min after the injection) after induction therapy
10. SUV collected during the examination, FDG-PET and [68Ga]Ga-PentixaFor-PET results (positive/negative).

Investigational products

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

Test 1

Comparator 1

Auxiliary 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Universitaire De Nantes

Sponsor organisation

Centre Hospitalier Universitaire De Nantes

Address

5 Allee De L Ile Gloriette

City

Nantes Cedex 1

Postcode

44093

Country

France

Scientific contact point

Organisation

Centre Hospitalier Universitaire De Nantes

Contact name

Caroline BODET-MILIN

Public contact point

Organisation

Centre Hospitalier Universitaire De Nantes

Contact name

Caroline BODET-MILIN

Locations

1 EU/EEA country · 4 investigational sites

By country

Investigational sites

Results and documents

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

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 2 files

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

Application history

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