| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 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 |
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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 |
The primary objectives are:
● Part 1: To identify RP2Ds for each treatment combination
● Part 2: To characterize the safety of each RP2D for each selected treatment combination(s)
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives are:
● To characterize the pharmacokinetics and pharmacodynamics of each study treatment
● To assess the immunogenicity of each study treatment
● To evaluate the antitumor activity of each treatment combination
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Each potential subject must satisfy all of the following criteria to be enrolled in the study:
1. ≥18 years of age.
2. Documented initial diagnosis of multiple myeloma according to International Myeloma Working Group (IMWG) diagnostic criteria
3. Must have either of the following:
● Received at least 3 prior lines of therapy (see definition below) including a PI (≥2 cycles or 2 months of treatment) and an IMiD (≥2 cycles or 2 months of treatment) in any order during the treatment (except for subjects who discontinued either of these treatments due to a severe allergic reaction within the first 2 cycles/months).
- Undergone at least 1 complete cycle of treatment for each line of therapy, unless progressive disease was the best response to the line of therapy.
OR
● Disease that is double refractory to a PI and an IMiD. For subjects who have received more than 1 type of PI, the disease must be refractory to the most recent one. Similarly, for those who have received more than 1 type of IMiD, the disease must be refractory to the most recent one.
NOTE: Subject must have documented evidence of progressive disease based on investigator’s determination of response by the IMWG 2016 criteria as described by Kumar et al. on or within 12 months of their last line of therapy. Confirmation may be from either central or local testing. Also, subjects with documented evidence of progressive disease (as above) within the previous 6 months and who are refractory or non-responsive to their most recent line of therapy afterwards are eligible.
NOTE: For subjects who are to be enrolled in a treatment combination that includes pomalidomide, prior IMiD therapy should include lenalidomide.
4. Measurable disease at screening as defined by any of the following:
● Serum monoclonal protein (M-protein)level ≥1.0 g/dL (in non-IgG myeloma, an M-protein level ≥0.5 g/dL);or
● Urine M-protein level ≥200 mg/24 hours; or
● Light chain multiple myeloma: Serum Ig free light chain (FLC) ≥10 mg/dL and abnormal serum Ig kappa lambda FLC ratio.
5. Eastern Cooperative Oncology Group (ECOG) performance status grade of 0 or 1 at screening and at Cycle 1, Day 1 predose.
6. Clinical lab values as stated in the protocol
7. Women of childbearing potential must have a negative highly -sensitive serum β human chorionic gonadotropin (β-hCG) pregnancy test (<5 IU/mL) at screening and a negative urine or serum pregnancy test within 24 hours before the first dose of study drug.
8. Women must be:
a. Not of childbearing potential b. Of childbearing potential and
– Practicing a highly effective, preferably user-independent method of contraception (failure rate of <1% per year when used consistently and correctly) and agrees to remain on a highly effective method while receiving study drug and until 100 days after last dose.
– Agree to pregnancy testing (serum or urine) within 100 days after the last study drug administration.
A woman using oral contraceptives must use an additional contraceptive method in addition to the requirements listed above.
9. Men must wear a condom when engaging in any activity that allows for passage of ejaculate to another person, during the study and for 100 days after the last dose of study drug. Male subjects should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak.
10. Women must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for at least 100 days after the last dose of study drug.
11. Men must agree not to donate sperm for the purpose of reproduction during the study and for at least 100 days after receiving the last dose of study drug.
12. 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 and able to participate in the study. Consent is to be obtained prior to the initiation of any study-related tests or procedures that are not part of standard-of-care for the subject’s disease.
13. Willing and able to adhere to the prohibitions and restrictions specified in this protocol.
Definition
• 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 steroids (ie, less than or equal to the equivalent of dexamethasone 40 mg/day for 4 days) would not be considered prior lines of therapy.
For complete inclusion criteria, please refer pages 67-69 of the protocol. |
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| E.4 | Principal exclusion criteria |
Any potential participant who meets any of the following criteria will be excluded from participating in the study:
1. Treatment in the prior 3 months with an anti-CD38 therapy (eg, daratumumab), or discontinuation of a prior anti-CD38 therapy at any time due to an adverse event related to the anti-CD38 therapy.
2. Prior antitumor therapy as follows, before the first dose of study drug:
• Targeted therapy, epigenetic therapy, or treatment with an investigational drug or an invasive medical device within 21 days or at least 5 half-lives, whichever is less.
• Monoclonal antibody treatment within 21 days (anti-CD38 treatment cannot be used within the prior 3 months
• Cytotoxic therapy within 21 days.
• PI therapy within 14 days.
• IMiD therapy within 7 days.
• Radiotherapy within 21 days. However, if the radiation portal covered ≤5% of the bone marrow reserve, the subject is eligible irrespective of the end date of radiotherapy.
• Gene modified adoptive cell therapy (eg, chimeric antigen receptor modified Tcells, NK cells) within 3 months
3. A cumulative dose of corticosteroids equivalent to ≥140 mg of prednisone within the 14-day period before the first dose of study drugs
4. Live, attenuated vaccine within 4 weeks prior to the first dose of study drug unless approved by sponsor.
5. Toxicity from previous anticancer therapy that has not resolved to baseline levels or to Grade ≤1 (except alopecia [any grade] or peripheral neuropathy Grade ≤3).
6. Stem cell transplantation:
• Subjects who received an allogeneic transplant must be off all immunosuppressive medications for >42 days without signs of graft-versus-host disease.
• Autologous stem cell transplantation ≤12 weeks before the first dose of study drug.
• An immunosuppressive drug (eg, cyclosporine, tacrolimus) within 28 days before the first dose of study drug.
7. Active central nervous system involvement or exhibits clinical signs of meningeal involvement of multiple myeloma. If either is suspected, brain magnetic resonance imaging (MRI) and lumbar cytology are required.
8. Active plasma cell leukemia (>2.0 x 10^9/L plasma cells by standard differential), Waldenström’s macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes), or primary amyloid light chain amyloidosis.
9. Known to be seropositive for human immunodeficiency virus.
10. Seropositive for hepatitis B (defined by a positive test for hepatitisB surface antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg negative with antibodies to total hepatitis B core antigen [Anti-HBc]
with or without the presence of hepatitis B surface antibodies [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: Subjects 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.
11. Active hepatitis C infection as measured by positive hepatitis C virus (HCV)-RNA testing. Subjects with a history of Hepatitis C virus antibody positivity must undergo HCV-RNA testing.
12. Either of the following:
• Chronic obstructive pulmonary disease (COPD) with forced expiratory volume in 1 second (FEV1) <50% of predicted normal. NOTE: FEV1 testing is required for subjects suspected of having COPD and subjects must be excluded if FEV1 is <50% of predicted normal.
• Moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any classification. NOTE: subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate in the study.
13. Allergies, hypersensitivity, or intolerance to any study intervention or its excipients (refer to Investigator’s Brochures and package inserts).
14. Any serious underlying medical condition, such as:
• Evidence of serious active viral, bacterial, or uncontrolled systemic fungal infection
• Active autoimmune disease or a history of autoimmune disease including any adverse events (resolved or active) related to prior immune or anticancer agents.
• Disabling psychiatric conditions (eg, alcohol or drug abuse), severe dementia, or altered mental status
• Any other issue that would impair the ability of the subject to receive, absorb, or tolerate the planned treatment at the investigational site, to understand informed consent or any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject(eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments
For complete exclusion criteria, please refer page 70-73 of the protocol. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Frequency and severity of dose-limiting toxicities
2. Frequency and severity of adverse events and serious adverse events
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Cycle 1 (28 days)
2. From the time of signing the ICF till 100 days after the last dose of study drug or until the start of subsequent systemic anticancer therapy, if earlier. |
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| E.5.2 | Secondary end point(s) |
1. Serum concentrations and pharmacodynamic markers
2. Presence of anti-drug antibodies
3. Overall response rate
4. Clinical benefit rate (minimal response or better)
5. Duration of and time to response |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Serum concentrations- Predose, Day (D) 1 of each cycle, End of treatment (EOT), follow-up
Pharmacodynamic markers- Part 1: Cycle (C) 1 D1, C1D9, C1D10, C1D11, C1D12, C1D15, C1D16, C1D22, C2D1, C3D1,C7D1
Pharmacodynamic markers- Part 2: C1D1, C1D9, C1D11, C1D15
2. Part 1 and Part 2 (Serum and Plasma): C1D1, C2D1, C4D1, C7D1, EOT, Post-treatment follow-up
3. Duration of the study
4. Duration of the study
5. Duration of the study |
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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 | 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 | Yes |
| 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 |
| Immunogenecity and biomarker assessment |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Dose escalation and dose expansion study |
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| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
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| 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 | 6 |
| 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 | 5 |
| 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 |
| Canada |
| United States |
| Germany |
| Netherlands |
| Spain |
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| 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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
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