| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed/Refractory Multiple Myeloma |
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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 | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 |
*Part 1 and Part 2 is conducted in the US only.
Part 1 Dose Escalation: To determine the safety and tolerability of single-agent modakafusp alfa in patients with RRMM.
Part 2 Expansion Cohorts: To provide a prelim. evaluation of the clinical activity of modakafusp alfa as a single agent and in comb. with dexamethasone in patients with RRMM.
Part 3 Extension Cohorts: To determine the objective response rate (ORR) as assessed by IRC according to IMWG criteria (App. F) of modakafusp alfa in patients who have MM defined by the IMWG criteria with evidence of progressive disease and are in need of additional myeloma therapy as determined by the investigator, have previously received at least 3 lines of myeloma therapy, and are refractory to at least 1 IMiD (ie, lenalidomide or pomalidomide [thalidomide excluded]), at least 1 PI (ie, bortezomib, ixazomib, or carfilzomib), and refractory to at least 1 anti-CD38 antibody and who have demonstrated progressive disease with the last therapy. |
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| E.2.2 | Secondary objectives of the trial |
Please see Protocol for full list of secondary objectives
Part 1 Dose Escalation:
To determine the MTD/OBD of modakafusp alfa with 1 or more schedules of administration.
To characterize the PK profile of modakafusp alfa.
To evaluate the immunogenicity of modakafusp alfa.
To provide a preliminary evaluation of the clinical activity of modakafusp alfa.
Part 2 Expansion:
To further evaluate safety and to determine the suitability of MTD/OBD of modakafusp alfa as a single agent and in combination with dexamethasone for further trials as the recommended dose and schedule.
To further characterize the PK profile of modakafusp alfa as a single agent and in combination with
dexamethasone.
To further characterize the immunogenicity of modakafusp alfa as a single agent and in combination with dexamethasone.
Part 3 Extension:
To determine ORR by investigator assessment, duration of response (DOR), clinical benefit rate (CBR), duration of clinical benefit, disease control rate (DCR),.. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
For Parts 1 and 2:
1. MM defined by the IMWG criteria with evidence of disease progression and:
a) Is in need of additional myeloma therapy as determined by the investigator.
b) Has previously received at least 3 lines of myeloma therapy (eg, containing an IMiD, a PI, an alkylating agent, and/or an anti-CD38 as single agents or in combination).
c) Is either refractory to, or intolerant of, at least 1 PI and at least 1 IMiD (see NOTE below).
For Part 3:
1. MM defined by the IMWG criteria with evidence of disease progression and:
a) Is in need of additional myeloma therapy as determined by the investigator.
b) Has previously received at least 3 lines of myeloma therapy.
c) Is refractory to at least 1 IMiD (ie, lenalidomide or pomalidomide [thalidomide excluded]), at least 1 PI (ie, bortezomib, ixazomib, or carfilzomib), and refractory to at least 1 anti-CD38 antibody (ie, daratumumab or isatuximab) and who have demonstrated disease progression during or after the last therapy (see NOTE below). Patients who were primary refractory to all previous therapies, meaning they never achieved at least a MR with any previous treatment line, are not eligible.
NOTE: Refractory is defined as ˂25% reduction in M-protein or progression of disease during treatment or within 60 days after cessation of treatment.
A line of therapy is defined as 1 or more cycles of a planned treatment program. This may consist of 1 or more planned cycles of single-agent therapy or combination therapy, as well as a sequence of treatments administered in a planned manner. A new line of therapy starts when a planned course of therapy is modified to include other treatment agents (alone or in combination) as a result of disease progression, relapse, or toxicity. A new line of therapy also starts when a planned period of observation off therapy is interrupted by a need for additional treatment for the disease (Rajkumar et al. 2011).
2. Aged 18 years or older.
3. For patients in Parts 2 and 3 only: Measurable disease defined as one of the following:
a) Serum M-protein ≥500 mg/dL (≥5 g/L).
b) Urine M-protein ≥200 mg/24 hours.
c) Serum free light chain (FLC) assay with involved FLC level ≥10 mg/dL (≥100 mg/L) provided serum FLC ratio is abnormal.
4. During Part 1 only, patients not meeting the above criteria for measurable disease should, at least, have measurable bone marrow plasmacytosis (≥10%) and/or plasmacytoma (≥1 cm in diameter) detected by physical examination or imaging.
5. ECOG performance status of ≤2.
6. Patient has adequate organ function as determined by the following laboratory values. See Protocol for values.
7. Female patients who:
Are postmenopausal for at least 2 years before the screening visit, OR
Are surgically sterile, OR
If they are of childbearing potential:
– Agree to practice 1 highly effective method of contraception and 1 additional effective (barrier) method at the same time, from the time of signing the informed consent through 7 days after the last dose of study
drug, OR
– Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject, from the time of signing the informed consent through 7 days after the last dose of study drug. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)
– Agree not to donate an egg or eggs (ova) during the study and for 7 days after the last dose of study drug.
8. Male patients, even if surgically sterilized (ie, status post vasectomy), who:
Agree to practice effective barrier contraception during the entire study treatment period and through 7 days after the last dose of study drug,
OR
Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)
Agree not to donate sperm during the study and for 7 days after the last dose of study drug.
9. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time
without prejudice to future medical care.
10. The patient must be willing and able to comply with study restrictions and to remain at the investigational center for the required duration during the study period and must be willing to return to the investigational center for the follow-up procedures and assessments specified in this protocol
Please see Protocol for full inclusion criteria |
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| E.4 | Principal exclusion criteria |
1. Patient has polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome, monoclonal gammopathy of unknown significance, smoldering myeloma, solitary plasmacytoma, amyloidosis, Waldenström macroglobulinemia or IgM myeloma, or lymphoplasmacytic lymphoma.
2. Patients who have received autologous SCT 60 days before first infusion of modakafusp alfa or patients who have received allogeneic SCT 6 months before first infusion.
3. Graft-versus-host disease that is active or requires ongoing systemic immunosuppression.
4. Part 1: Until the MTD/OBD is defined, patients who have received daratumumab (or other investigational anti-CD38 antibody) for at least 5 months (steady state) require a 90-day wash-out period before receiving modakafusp alfa. For patients who have received less than 5 months of daratumumab or who have received another anti-CD38 monoclonal antibody, the necessary wash-out period needs to be discussed and approved by the sponsor. Once the MTD/OBD has been confirmed, these patients can be enrolled in the trial (Parts 2 and 3).
Parts 2 and 3: No washout from daratumumab or isatuximab is required.
5. Patient has not recovered from adverse reactions to prior myeloma treatment or procedures (chemotherapy, immunotherapy, radiation therapy) to National Cancer Institute Common
Terminology Criteria for Adverse Events (NCI CTCAE) Grade ≤1 or baseline, except for sensory or motor neuropathy which should have recovered to Grade ≤2 or baseline.
6. Patient has received the final dose of any of the following treatments/procedures within the specified minimum intervals before the first dose of modakafusp alfa. See Protocol for values.
7. Patient has congestive heart failure (New York Heart Association Grade ≥II), cardiac
myopathy, active ischemia, or any other uncontrolled cardiac condition such as angina
pectoris, clinically significant arrhythmia requiring therapy including anticoagulants, or
clinically significant uncontrolled hypertension.
8. Patient has a history of acute myocardial infarction within 5 months from enrollment or has electrocardiogram (ECG) abnormalities during screening that are deemed medically relevant by the investigator.
9. Patient has QT interval corrected by the Fridericia method (QTcF) >480 msec (Grade ≥2).
10. Patient has a concurrent illness that would preclude study conduct and assessment including, but not limited to, uncontrolled medical conditions, uncontrolled and active infection (considered opportunistic, life-threatening, or clinically significant), uncontrolled risk of bleeding, uncontrolled diabetes mellitus, pulmonary disease (including obstructive pulmonary disease, pulmonary fibrosis, and history of symptomatic bronchospasm), alcoholic liver disease, or primary biliary cirrhosis.
11. Patient has a chronic condition requiring the use of systemic corticosteroids >10 mg/day of
prednisone or equivalent.
12. Patient has clinical signs of central nervous system involvement of MM.
13. Female patients who are lactating and breastfeeding or have a positive serum pregnancy test during the screening period or a positive urine pregnancy test on Day 1 before first dose of study drug if applicable.
14. Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of treatment according to this protocol.
15. Patient has a known history of human immunodeficiency virus.
16. Parts 1 and 2: Known chronic hepatitis C and/or positive serology (unless due to vaccination or
passive immunization due to Ig therapy) for chronic hepatitis B.
Japan Safety Lead-In and Part 3: Known chronic hepatitis C and/or positive serology for chronic hepatitis B (unless due to vaccination or passive immunization due to Ig therapy), or hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]. Participants with resolved infection (that is, 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 HBV DNA levels. Those who are PCR positive will be excluded [...].
Please see Protocol for full list of exclusion criteria
Part 3: In addition to the above criteria, patients must not have plasma cell leukemia or have had primary refractory MM, current central nervous system involvement of MM, myelodysplastic
syndrome, myeloproliferative syndrome, or have had a second malignancy within the previous
3 years, except treated basal cell or localized squamous skin carcinomas, localized prostate cancer,
cervical carcinoma in situ, resected colorectal adenomatous polyps, breast cancer in situ, or other
malignancy for which the patient is not on active anticancer therapy. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Part 1 Primary Endpoints:
The number of patients with TEAEs overall and per dose level.
Patients with DLTs at each dose level.
Patients with Grade >=3 TEAEs.
Patients with serious adverse events (SAEs).
Patients who discontinue because of TEAEs.
Patients with dose modifications (delays, interruptions, dose reductions).
Part 2 Primary Endpoints:
ORR, defined as the proportion of patients who achieved a PR or better during study; sCR, CR, VGPR, and PR as defined by IMWG Uniform Response Criteria (Appendix F).
Part 3 Primary Endpoint:
ORR (PR or better) assessed by IRC according to modified IMWG criteria (Appendix F).
Clinically significant laboratory values.
Clinically significant vital sign measurements. |
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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) |
Part 1 Secondary Endpoints
DLT-like (TEAEs meeting DLT definition that occur after phase 1 Cycle 1) frequencies and other TEAEs occurring over the course of extended treatment with modakafusp alfa, including information about dose modification, treatment discontinuation, and clinically significant laboratory values and vital signs.
Summary statistics by dose level and cycle day for the following PK parameters:
– Single-dose Cmax.
– Time of first occurrence of Cmax (tmax).
– Area under the serum concentration-time curve from time 0 to infinity (AUC∞).
– Area under the serum concentration-time curve from time 0 to time of the last quantifiable concentration (AUClast). Apparent serum modakafusp alfa terminal disposition rate constant (λz).
– Apparent serum modakafusp alfa terminal elimination phase half-life (t1/2z).
– CL.
– Volume of distribution at steady state (Vss).
Antimodakafusp alfa-antibody incidence and characteristics (eg, titer and specificity).
Preliminary evaluation of antitumor activity of modakafusp alfa:
– For patients with measurable disease only: ORR, defined as the proportion of patients who achieved a P or better during the study; sCR, CR, very good partial response (VGPR), and PR as defined by IMWG Uniform Response Criteria (Appendix F), CBR (includes patients with a response of sCR, CR, VGPR, PR, or minimal response); DCR (includes patients with a response of sCR, CR, VGPR, PR, minimal response, or stable disease).
– For patients with measurable disease only: median DOR, with DoR defined as the time from the date of first documentation of response PR or better to the time of disease progression or death, whichever occurs first.
– For patients with measurable disease only: time to response, defined as the time from first dose to the date of first documentation of response (PR or better).
– Progression-free survival (PFS), defined as the time from the date of first dose until the sooner of the date of PD, defined by IMWG criteria (Appendix F), or the date of death due to any cause.
Part 2 Secondary Endpoints
DOR.
CBR.
DCR.
PFS, defined as the time from the date of first dose until the sooner of the date of PD, defined by IMWG criteria (Appendix F), or the date of death due to any cause.
OS, defined as the date from first dose to the date of death due to any cause.
Time to response, defined as the time from first dose to the date of first documentation of response (PR or better).
DLT-like events (TEAEs meeting DLT definition that occur after Part 1 Cycle 1) frequencies and other TEAEs occurring over the course of extended treatment with modakafusp alfa, including information about dose modification, treatment discontinuation, and clinically significant laboratory values and vital signs.
Summary statistics by dose level and cycle day for the following PK parameters: Cmax, AUC∞,AUClast, λz, tmax, CL, Vss, and t1/2z.
Anti–modakafusp alfa antibody incidence and characteristics (eg, titer and specificity).
Part 3 Secondary Endpoints
ORR by investigator assessment.
DOR.
CBR (response of sCR, CR, VGPR, PR, or minimal response) by IRC and investigator assessment.
Duration of clinical benefit.
DCR (CBR + stable disease [SD]) by IRC and investigator assessment.
Duration of disease control.
PFS (time from the date of first dose until the sooner of the date of PD, defined by IMWG criteria [(Appendix F)] or the date of death due to any cause by IRC and investigator assessment.
TTP by IRC and investigator assessment.
OS (date from first dose to the date of death due to any cause).
Rate of MRD negative status at a sensitivity of 10-5 in patients achieving CR.
Duration of MRD negativity at a sensitivity of 10-5 in patients achieving CR.
AEs, SAEs, laboratory assessments, supportive care use.
Eastern Cooperative Oncology Group (ECOG) status.
ADA incidence and characteristics (eg, titer and specificity) and neutralizing antibody (nAb).
Length of hospital stay, types of hospital stay, and other healthcare utilization data as defined in Section 9.3.15.
No worsening of disease symptoms (includes bone aches or pain, back pain, hip pain, arm or shoulder pain, chest pain, and pain increasing with activity) from baseline at 12 weeks across doses of modakafusp alfa as measured by the patient-reported outcome (PRO) instrument European Organisation for Research and Treatment of Cancer QLQ Questionnaire Multiple Myeloma Module (EORTC QLQ-MY20). |
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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 | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
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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 | Yes |
| 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.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 35 |
| 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 |
| Taiwan |
| Canada |
| China |
| Israel |
| Japan |
| Korea, Republic of |
| United Kingdom |
| United States |
| Czechia |
| France |
| Germany |
| Greece |
| Ireland |
| Italy |
| Norway |
| Spain |
| Türkiye |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| 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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| The final analysis for the clinical study report will be conducted after all patients enrolled in the study have completed OS follow-up or have withdrawn from the study. |
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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 | 7 |
| 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 | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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