| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective is to compare the efficacy (rate of very good partial response [VGPR] or better as best response as defined by the International Myeloma Working Group [IMWG] criteria) of Dara-SC in combination with Kd with the efficacy of Kd in participants with relapsed refractory multiple myeloma who were previously exposed to daratumumab to evaluate daratumumab retreatment.
|
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives are:
• To further characterize the efficacy (progression-free survival [PFS], overall survival [OS], overall response rate [ORR], rate of complete response[CR]/stringent complete response [sCR]) of Dara-SC in combination with Kd
• To evaluate the minimal residual disease (MRD) negativity rate and durability of MRD negativity status
• To characterize the safety of Dara-SC in combination with Kd
• To determine time to next treatment
• To evaluate the pharmacokinetics (PK)of Dara-SC
• To determine the immunogenicity of daratumumab recombinant human hyaluronidase PH20 (rHuPH20)
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. At least 18 years of age.
2.1 Measurable disease at screening as defined by any of the following: Serum M-protein level ≥1.0 g/dL in participants with immunoglobulin G
(IgG) type, or serum M-protein level ≥0.5 g/dL in participants with non-IgG type, or urine M-protein level ≥200 mg/24 hours; or Light chain multiple myeloma without measurable disease in the serum or the urine: Serum immunoglobulin free light chain (FLC) ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda FLC ratio.
3.1 Evidence of a response (partial response or better based on investigator's determination of response by IMWG criteria) to daratumumab-containing therapy with response duration of at least 4 months.
4.1 Participants must have progressed from or be refractory to their last line of treatment. Relapsed or refractory disease as defined below:
Relapsed disease is defined as an initial response to previous treatment, followed by confirmed PD by IMWG criteria >60 days after cessation of
treatment. Refractory disease is defined as <25% reduction in M-protein or confirmed PD by IMWG criteria during previous treatment or 60 days after cessation of treatment.
5.1 Received 1 to 3 prior line(s) of treatment of which one contained daratumumab and completed daratumumab at least 3 months prior to
randomization. A single line of therapy may consist of 1 or more agents, and may include induction, hematopoietic stem cell transplantation, and maintenance therapy. Radiotherapy, bisphosphonate, or a single short course of corticosteroids (no more than the equivalent of dexamethasone
6. ECOG Performance Status score of 0, 1, or 2.
7. Pretreatment clinical laboratory values meeting the following criteria during the Screening Phase:
a) hemoglobin ≥8 g/dL (≥5mmol/L) (without prior RBC transfusion within 7 days before the laboratory test; recombinant human erythropoietin use is permitted);
b) absolute neutrophil count (ANC) ≥1.0 × 10^9/L (prior growth factor support is permitted but must be without support within the 7 days prior to the laboratory test);
c) platelet count ≥75 ×10^9/L for participants in whom <50% of bone marrow nucleated cells are plasma cells; otherwise platelet count of ≥ 50×10^9/L. Transfusions are not permitted within 7 days of testing to achieve this minimum platelet count. Please see the complete list of criteria 7 in Protocol Am on pg.39
8.1 Women of childbearing potential must commit to either abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously. This includes one highly effective form of contraception (tubal ligation, intrauterine device, hormonal [birth control pills, injections, hormonal patches, vaginal rings or implants] or partner's vasectomy) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). A reduction in the effectiveness of oral contraceptives during carfilzomib treatment cannot be excluded. In addition, because of the increased risk of venous thromboembolic events associated with carfilzomib, women should avoid the use of hormonal contraceptives that are associated with a risk of thrombosis during treatment with carfilzomib. Women of childbearing potential who are using oral contraceptives or a hormonal method of contraception that is associated with a risk of thrombosis should switch to an alternative method of
highly effective contraception. Contraception must begin with study treatment initiation and continue for 3 months after discontinuing study
treatment. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for a period of 3 months
after receiving the last dose of any component of the study treatment. Male participants who are sexually active with women of childbearing potential or with pregnant women must always use a latex or synthetic condom during the study and for 3 months after discontinuing study treatment (even after a successful vasectomy). Male participants of reproductive potential must not donate sperm during the study or for 3 months after the last dose of study treatment.
9. Women of childbearing potential must have a negative urine or serum pregnancy test at screening within 14 days prior to randomization.
10.1 Each participant must sign an informed consent form (ICF) indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study. Participants must be willing and able to adhere to the prohibitions and
restrictions specified in this protocol, as referenced in the ICF. |
|
| E.4 | Principal exclusion criteria |
Any potential participant who meets any of the following criteria will be excluded from participating in the study:
1. Criterion deleted per Amend 2
2. Previoustreatment with carfilzomib.
3. Previous treatment with daratumumab within the last 3 months prior to randomization.
4.1 Discontinuation of daratumumab due to a daratumumab-related AE.
5. Allergies, hypersensitivity, or intolerance to daratumumab, hyaluronidase, mAbs, human proteins, or their excipients (refer to the IB), or known sensitivity to mammalian derived products. Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib).
6. Contraindications to the use of any components of the backbone treatment regimens, per local prescribing information.
7. Received an investigational intervention (including investigational vaccines) or used an invasive investigational medical device within 4 weeks before randomization (except for investigational anti-myeloma treatments, which cannot be taken within 2 weeks or 5PK half-lives of the treatment from the first dose of daratumumab, whichever is longer, before the date of randomization).
8.1 Received an investigational intervention (including investigational vaccines) or used an invasive investigational medical device within 4 weeks before randomization (except for investigational anti-myeloma treatments, which cannot be taken within 2 weeks or 5 PK half-lives of the treatment from the date of randomization, whichever is longer)9. Pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or within 3 months after the last dose of study intervention.
10. Plans to father a child while enrolled in this study or within 3 months after the last dose of study intervention.
11. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise the
12.1. Received anti-myeloma treatment within 2 weeks or 5 PK half-lives of the treatment from the date of randomization, whichever is longer. The only exception is emergency use of a short course of corticosteroids (equivalent of dexamethasone 40 mg/day for a maximum of 4 days; see Appendix 10) up to 21 days before treatment. A list of anti-myeloma treatments with the corresponding PK half-lives is provided in the Site Investigational Product Procedures Manual.
13. Received autologous stem cell transplant within 12 weeks before the date of randomization, or the participant has previously received allogeneic stem cell transplant (regardless of timing).
14. Plans to undergo a stem cell transplant prior to progression of disease on this study.
15. Focal radiation therapy within 14 days prior to randomization with the exception of palliative radiotherapy for symptomatic management but not on measurable extramedullary plasmacytoma. Radiotherapy within 14 days prior to randomization on measurable extramedullary plasmacytoma is not permitted even in the setting of palliation for symptomatic management.
16. Clinical signs of meningeal involvement of multiple myeloma.
17. Please see the protocol for exlusion criteria 17.
18.1 Participant is:
a) known to be seropositive for human immunodeficiency virus (HIV), with 1 or more of the following:
i. Not receiving highly active antiretroviral therapy (ART)
ii. Had a change in ART within 6 months of the start of screening
iii. Receiving ART that may interfere with study treatment (consult Sponsor for review of medication prior to enrollment)
iv. CD4 count <350 at screening
v. Acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection within 6 months of start of screening
vi. Not agreeing to start ART and be on ART >4 weeks plus having HIV viral load <400 copies/mL at end of 4-week period (to ensure ART is tolerated and HIV controlled)
b) seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Participants with resolved infection (ie, participants who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded.
EXCEPTION: Participants with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR.
c) known to be seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy).
For full exclusion criteria, refer to page no: 40 to 44 of the protocol
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The rate of very good partial response (VGPR) or better as defined by the IMWG criteria.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Randomization to death, disease progression ( DP) , or lack of VGPR after 16 cycles of treatment (approximately 1 year and 3 months) |
|
| E.5.2 | Secondary end point(s) |
1. Overall response rate (ORR) [rate of partial response (PR), very good partial response (VGPR), complete response (CR), stringent complete response (sCR)]
2. Rate of CR/sCR
3. Progression free survival (PFS)
4. Overall survival (OS)
5. Minimal residual disease (MRD) negativity rate
6. Time to next treatment
7. Serum daratumumab concentrations
8. Prevalence and incidence of anti-daratumumab antibodies and anti-rHuPH20 antibodies
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.Randomization (R) to death, DP or lack of VGPR/PR/CR/sCR after 16 cycles (C) of treatm.(about 1 yr and 3 mths)
2.R to death, DP or lack of CR/sCR after 16 C of treatment (about 1 yr and 3 months)
3.From R to PFS after about 18.7 mths
4.From R to end of study(defined as no later than 2 yrs after the last participant has received their initial dose of study intervention or when the sponsor decides to stop the study)
5.Bone marrow aspirates will be collected at time of suspected CR/sCR and for participants achieve CR,have not progressed, and remain on the study,additional bone marrow aspirate will be obtained at 12,18 and 24 mth post C1Day1
6.From R to next Myeloma treatm.(about 16 C)
7.Arm A: C1, C3; Arm B: C1,C3,C7 and Post-treatm. Wk8
8.Arm A: C1; Arm B: C1,C7 and Post-treatm. Wk8 |
|
| 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 | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Immunogenicity and Biomarker analyses |
|
| 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 | 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.8.2.4 | 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 65 |
| 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 |
| Brazil |
| Canada |
| Russian Federation |
| United States |
| Belgium |
| Denmark |
| France |
| Germany |
| Italy |
| Netherlands |
| Poland |
| Spain |
| Greece |
|
| 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
|
| The end of study is no later than 2 years after the last participant has received their initial dose of study intervention or when the sponsor decides to stop the study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
Print
