E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Elderly Relapse Refractory Multiple Myeloma Patients |
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E.1.1.1 | Medical condition in easily understood language |
Elderly Relapse Refractory Multiple Myeloma Patients |
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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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10028228 |
E.1.2 | Term | Multiple myeloma |
E.1.2 | System Organ Class | 100000004864 |
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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 |
determine the Very Good Partial Response (VGPR) + Complete response (CR) rate to Ixazomib plus Daratumumab in RR MM |
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E.2.2 | Secondary objectives of the trial |
· To determine Safety of Ixazomib plus Daratumumab (type, frequency, severity, and relationship of adverse events to study treatment). Incidence of Treatment Emergent Adverse Event , Serious Adverse Event and laboratory abnormalities using National Cancer Institute common toxicity criteria · To determine the clinical benefit rate (CBR, Minor response or better). MR will be determined using the criteria of the European Organisation for Blood and Marrow Transplantation criteria · To determine ORR including Partial Response (PR), Very Good Partial Response , Complete Response and minor response (MR) to Daratumumab plus Ixazomib at 3 months and 6 months of treatment · To determine progression-free survival · To determine time to progression · To determine time to response · To determine the Duration of Response · To determine Overall Survival · To determine difference in response rates and survival according to prior exposure to VMP versus RD · To assess Quality of Life
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Must be able to understand and voluntarily sign an informed consent form 2. Must be able to adhere to the study visit schedule and other protocol requirements 3. Age >= 65 years 4. Subjects affiliated with an appropriate social security system. 5. Life expectancy > 6 months 6. Patients must have relapsed myeloma, and have been previously treated with Bortezomib, Melphalan and Prednisone (VMP) or Lenalidomide and Dexamethasone (Rd), or both: 7. Patients must have a clearly detectable and quantifiable monoclonal M-component value: IgG (serum M-component > 10g/l) IgA (serum M-component > 5g/l) IgD (serum M-component > 0.5g/l) Light chain (serum M-component >1g/l or Bence Jones > 200 mg/24H) In patients without measurable serum and urine M-protein levels when the absolute serum Free Light chain (sFLC) is ≥100 mg/l and an abnormal sFLC K/λ ratio (<0.26 and >1.65) is found (Dispenzieri, 2008). 8. Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2 9. Adequate bone marrow function within 5 days prior to 1st drug intake (cycle1, day 1, C1D1), without transfusion nor growth factor support within 5 days prior to 1st drug intake, defined as: Absolute neutrophils ≥ 1000/mm3 Platelets ≥ 50000/mm3 Haemoglobin ≥ 8.5g/dl 10. Adequate organ function defined as: Serum creatinine clearance (MDRD formula) ≥30 ml/min Serum SGOT or SGPT < 3.0 X upper limit of normal (ULN) Serum total bilirubin < 2.0 mg/dL 11. Wash out period of at least 2 weeks from previous antitumor therapy or any investigational treatment or 5 half-lives from previous antibodies. 12. Women who are partners of men and of childbearing potential must be practicing one of the following methods of birth control: subcutaneous hormonal implant, levonorgestrel releasing intra-uterine system, medroxyprogesterone acetate depot, tubal sterilization, ovulation inhibitory progesterone only pills, or sexual intercourse with a vasectomized male partner (vasectomy must be confirmed by 2 negative semen analyses). Or women will commit to absolute and continuous abstinence confirmed to her physician on a monthly basis. Childbearing potential*. Contraception will start during therapy including dose interruptions, for 4 months after discontinuation of Ixazomib and Daratumumab. 13. A woman of childbearing potential must have 2 negative serum or urine pregnancy tests at Screening, first within 28 days prior to dosing and the second within 48 hours prior to dosing, and remain on a highly effective method of birth control. The two methods of reliable contraception must include one highly effective method and one additional effective (barrier) method. FCBP must be referred to a qualified provider of contraceptive methods if needed. The following are examples of highly effective and additional effective methods of contraception: · Highly effective methods: Intrauterine device (IUD) Hormonal (birth control pills, injections, implants) Tubal ligation Partner’s vasectomy · Additional effective methods: Male condom Diaphragm CervicalCap 14. Serum (urine in the case where serum is not possible in a timely manner) pregnancy test to be performed for all women of childbearing potential regularly during the study, In addition, a pregnancy test may be done at any time during the study at the discretion of the investigator if a subject misses a period or has unusual menstrual bleeding. 15. A woman of childbearing potential must remain on a highly effective method of birth control. Contraception must begin 4 weeks before initiating treatment with Ixazomib and Daratumumab, during therapy, during dose interruptions and continuing for 4 months following discontinuation of Ixazomib and Daratumumab. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. 16. A man who has not had a vasectomy and who is sexually active with a woman of childbearing potential must agree to use a barrier method of birth control eg, condom with spermicidal foam/gel/film/cream/suppository, and all men must also not donate sperm during the study, for 4 months following discontinuation of Ixazomib and Daratumumab. The exception to this restriction is that if the subject’s female partner is surgically sterile, a second method of birth control is not required.
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E.4 | Principal exclusion criteria |
1. Target disease exceptions: · Solitary bone/solitary extramedullary plasmocytoma · Patients with non-secretory MM and non-measurable MM · Evidence of central nervous system (CNS) involvement 2. Medical history and Concurrent disease: · Subjects with prior (≤ 5 years) or concurrent invasive malignancies except the following: Adequately treated basal cell or squamous cell skin cancer Incidental finding of low grade (Gleason 3+3 or less) prostate cancer Any cancer from which the subject has been disease free for at least 3 years. · Subject with known/underlying medical conditions that, in the investigator’s opinion would make the administration of the study drug hazardous (ie: uncontrolled diabetes or uncontrolled coronary artery disease) · Any uncontrolled or severe cardiovascular or pulmonary disease determined by the investigator including: NYHA functional classification III or IV congestive heart failure LVEF (Left Ventricular Ejection Fraction) ≥45% Uncontrolled angina, hypertension or arrhythmia Myocardial infarction in the past 6 months · Subjects with grade 2 or greater peripheral neuropathy (as per NCI-CTCAEv4.0) · Subject is a woman who is pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or within 4 months after the last dose of any component of the treatment regimen. Or, subject is a man who plans to father a child while enrolled in this study or within 4 months after the last dose of any component of the treatment regimen. · Known positive for HIV or active hepatitis B or C. · Subjects with psychiatric illnesses or social situations that would preclude them understanding the informed consent, study compliance or the ability to tolerate study procedures and/or study therapy · Subjects with known chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) < 50% of predicted normal. Note that FEV1 testing is required for patients suspected of having COPD and subjects must be excluded if FEV1 <50% of predicted normal. · Subjects with a history of moderate or severe persistent asthma within the past 2 years (see appendix), 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). · Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of Ixazomib including difficulty swallowing. 3. Physical and laboratory test findings: · Patients on dialysis or with a Creatinine clearance < 30mL/min · SGOT or SGPT >3ULN 4. Prohibited prior therapies · Prior local irradiation within two weeks before first dose · Previous anti-CD38 therapy. · Previous Ixazomib therapy 5. Allergies and Adverse Drug Reaction: Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent. 6. Refusal to consent or protected by a legal regime (guardianship, trusteeship)
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the Very Good Partial Response (VGPR) + Complete Response (CR) Rate using the IMWG response criteria. Using IMWG criteria for best response reached at any time |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
· Assess safety by type, frequency, severity, relationship of adverse events to study treatment and changes in vital signs, physical exams. Incidence of Treatment Emergent Adverse Event (TEAE), Serious Adverse Event (SAE) and laboratory abnormalities using National Cancer Institute (NCI) common toxicity criteria (CCTAE V4). · Determine the Clinical Benefit Rate (CBR = sCR + CR + PR + MR), and duration of Clinical Benefit using EBMT criteria at 3 months and six months. · Determine the OS (from the date of inclusion to last date of follow-up) of patients treated with Ixazomib + Daratumumab, Progression-free Survival (PFS), Event-free Survival (EFS) and time to progression (TTP). · Secondary efficacy variables for study treatment include: o Time to progression (TTP) obtained with study treatment versus the patient’s TTP(s) on prior therapies for MM o Duration of Response (DOR) · Assess QoL using EORTC QLQ30, MY20 and EQ5D-3L · Compare PFS, ORR, DOR, DCR, and OS obtained with Ixazomib plus Daratumumab and in patients with International Staging System (ISS) Stages II/III versus ISS Stage I at diagnosis
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
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 | 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.8.3 |
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 | 30 |
E.8.5 | The trial involves multiple Member States | No |
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 | 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
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Last Visit of the Last Subject |
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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 | 5 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |