| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Aggressive and Indolent B-cell Malignancies |
|
| E.1.1.1 | Medical condition in easily understood language |
| Phase II Signal Finding Study in B-Cell Malignancies |
|
| 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 | PT |
| E.1.2 | Classification code | 10061275 |
| E.1.2 | Term | Mantle cell lymphoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10008976 |
| E.1.2 | Term | Chronic lymphocytic leukemia |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 27.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10085128 |
| E.1.2 | Term | Follicular lymphoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10058728 |
| E.1.2 | Term | Richter's syndrome |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
1. To evaluate the safety and tolerability of zilovertamab vedotin
2. To evaluate the safety and tolerability of zilovertamab vedotin in combination with nemtabrutinib
3. To evaluate zilovertamab vedotin with respect to objective response rate
4. To evaluate zilovertamab vedotin in combination with nemtabrutinib with respect to objective response rate
|
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate zilovertamab vedotin with respect to duration of response
2. To evaluate zilovertamab vedotin in combination with nemtabrutinib with respect to duration of response
3. To evaluate the safety and tolerability of zilovertamab vedotin
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. For aggressive B-cell malignancies:
• Cohort A:
a. Has biopsy proven histologically confirmed MCL.
AND
b. Has relapsed or refractory disease after at least 2 prior systemic therapies
• Cohort B:
a. Has biopsy proven histologically confirmed RT
AND
b. Has relapsed or refractory disease after at least 1 prior systemic therapy.
• Cohort C:
a. Has biopsy proven histologically confirmed MCL
AND
b. Has relapsed or refractory disease after at least 1 prior systemic therapy, has no prior exposure to a non-covalent BTKi.
2. For indolent B-cell malignancies, Part 1:
• Cohort D:
a. Has biopsy proven histologically confirmed FL Grade 1-3A
AND
b. Has relapsed or refractory disease after at least 2 prior systemic therapies and no other available therapy.
OR
c. Has histologically confirmed CLL
AND
d. Has relapsed or refractory disease after at least 2 prior systemic therapies and no other available therapy.
3. For indolent B-cell malignancies, Part 2:
• Cohort E:
a. Has biopsy proven histologically confirmed FL Grade 1-3A
AND
b. Has relapsed or refractory disease after at least 2 prior systemic therapies and no other available therapy.
• Cohort F:
a. Has histologically confirmed CLL
AND
b. Has relapsed c or refractory d disease after at least 2 prior systemic therapies and no other available therapy.
4. Disease status requirements:
• For Cohorts A and B:
a. Has PET positive disease verified by BICR at Screening
b. Has radiographically measurable disease per the Lugano Response Criteria, as assessed locally by the investigator and verified by BICR.
• For Cohort C:
a. Has PET positive assessed locally by investigator at Screening, defined as 4-5 on the Lugano 5-point scale.
b. Has radiographically measurable disease per the Lugano Response Criteria
• For Cohort D and E:
a. Has radiographically measurable disease per the Lugano Response Criteria, OR
b. Has PET positive disease verified by BICR at Screening defined as 4-5 on a 5-point scale.
• For Cohorts D, and F: symptomatic disease that mandates treatment
• For Cohorts D (FL) and E: clinical features that mandate treatment such as high tumor burden according to the modified GELF criteria.
5. Participants who are HbsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization.
6. Participants with history of HCV infection are eligible if HCV viral load is undetectable at Screening.
7. Is male or female, from 18 years of age inclusive, at the time of providing informed consent.
8. If male, agrees to the following during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention. The length of time required to continue contraception for each study intervention is as follows:
- Zilovertamab vedotin: 110 days
- Nemtabrutinib: 12 days
• Refrains from donating sperm
PLUS either:
• Abstains from heterosexual intercourse as their preferred and usual lifestyle and agrees to remain abstinent OR
• Uses contraception unless confirmed to be azoospermic
9. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
• Not a WOCBP
OR
• A WOCBP and:
- Uses a contraceptive method that is highly effective, with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle. The length of time required to continue contraception for each study intervention is as follows:
◦ Zilovertamab vedotin: 50 days
◦ Nemtabrutinib: 30 days
- Has a negative highly sensitive pregnancy test within 24 hours for urine and 72 hours for serum before the first dose of study intervention with zilovertamab vedotin and at least 30 days after
study intervention with nemtabrutinib.
- Abstains from breastfeeding during the study intervention period and for at least 20 days after study intervention.
- Medical history, menstrual history, and recent sexual activity has been reviewed by the investigator to decrease the risk for inclusion of a woman with an early undetected pregnancy.
10. The participant has provided documented informed consent for the study. May also provide consent for FBR.
11. For Cohorts A, B, C, D and E: Has provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated has been provided. Archival tissue must have been collected <5 years prior to Screening.
12. Have an ECOG performance status of 0 to 2 assessed within 7 days before C1D1.
13. Prior exposure to MMAE-containing drugs is allowed.
14. Have adequate organ function. Specimens must be collected and reviewed within 7 days before the start of study intervention. |
|
| E.4 | Principal exclusion criteria |
1. Has received solid organ transplant at any time.
2. Has clinically significant (ie, active) cardiovascular disease: cerebral vascular accident/stroke (<6 months prior to enrollment), myocardial infarction (<6 months prior to enrollment), unstable angina (<6 months prior to enrollment), congestive heart failure (New York Heart Association Classification Class ≥ II), or serious cardiac arrhythmia requiring medication.
3. In participants with prior allo-SCT, acute GVHD or ongoing evidence of chronic GVHD manifesting as Grade ≥2 serum bilirubin, Grade ≥3 skin involvement, or Grade ≥3 diarrhea or requiring systemic immunosuppression for treatment/prophylaxis for their GVHD.
4. Has pericardial effusion or clinically significant pleural effusion.
5. Has ongoing Grade >1 peripheral neuropathy.
6. Has a demyelinating form of Charcot-Marie-Tooth disease.
7. Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years.
8. Participants with FL who have transformed to a more aggressive type of lymphoma.
9. Has received prior therapy with a ROR1-directed therapy.
10. Has contraindication to any of the study intervention components.
11. Has received prior systemic anticancer therapy, within 5 half-lives or 4 weeks if prior therapy was a monoclonal antibodies or 2 weeks if prior therapy was small molecules like kinase inhibitors prior to the first dose of study intervention.
12. Has received prior radiotherapy within 28 days of start of study intervention. Participants must have recovered from all radiation-related toxicities.
A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
13. Has ongoing corticosteroid therapy exceeding 30 mg daily of prednisone equivalent.
If taken, prednisone equivalent dosing of ≤30 mg daily must have been stable for at least 4 weeks prior to C1D1 unless corticosteroid treatment is required for lymphoma symptom control prior to C1D1. In that case, up to 100 mg per day of prednisone equivalent can be given for up to 5 days, and tumor assessments must have been completed prior to the start of corticosteroid treatment.
14. Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed.
15. Has received a strong inhibitor or inducer of CYP3A4 (including itraconazole, ketoconazole, posaconazole, or voriconazole) within 7 days prior to C1D1 or expected requirement for chronic use of a strong CYP3A4 inhibitor or inducer during the study intervention period and for 30 days after the last dose of study intervention.
16. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks before the first dose of study intervention.
17. Has known active CNS lymphoma involvement or active CNS involvement by lymphoma. Participants with prior CNS involvement are eligible if their CNS disease is in radiographic, cytological (for cerebrospinal fluid disease) and clinical remission.
18. Has an active infection requiring systemic therapy.
19. Has a known history of HIV infection. No HIV testing is required unless mandated by local health authority.
20. Active HBV or HCV infection.
21. Has a history or current evidence of any condition, therapy, or laboratory abnormality, or other circumstance that might confound the results of the study, interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator.
22. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study.
Other Exclusions
23. Has QTc prolongation (defined as a QTcF >450 msecs) or other significant ECG abnormalities including second degree AV block type II, third degree AV block, or bradycardia (ventricular rate less than 50 beats/min).
24. Is currently being treated with the following drugs:
- CYP2C8 substrates with a narrow therapeutic index (such as paclitaxel)
- P-gp substrates with a narrow therapeutic index (such as digoxin)
- CYP3A strong inducers and inhibitors
25. Has any clinically significant gastrointestinal abnormalities that might alter absorption. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Percentage of participants with ≥1 adverse event (AE) [Cohorts C and D]
2. Percentage of participants discontinuing from study therapy due to AE (Cohorts C and D)
3. Percentage of participants with dose-limiting toxicity (DLT) [Cohort C]
4. Objective response rate (ORR) per Lugano Response Criteria as assessed by blinded independent central review (BICR)
5. ORR per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Criteria as assessed by investigator |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 57 months
2. Up to approximately 57 months
3. Up to approximately 57 months
4. Up to approximately 57 months
5. Up to approximately 57 months |
|
| E.5.2 | Secondary end point(s) |
1. Duration of response (DOR) per Lugano Response Criteria as assessed by BICR
2. DOR per iwCLL Criteria as assessed by investigator
3. Percentage of participants with ≥1 AE (Cohorts A, B, E, and F)
4. Percentage of participants discontinuing from study therapy due to AE (Cohorts A, B, E, and F) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 57 months
2. Up to approximately 57 months
3. Up to approximately 57 months
4. Up to approximately 57 months |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Patient reported outcome; Anti-Drug Antibody testing, Receptor occupancy |
|
| 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 | Yes |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 26 |
| 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 |
| Chile |
| Malaysia |
| Peru |
| Singapore |
| Brazil |
| Canada |
| Israel |
| Korea, Republic of |
| Russian Federation |
| United Kingdom |
| United States |
| Czechia |
| Estonia |
| Germany |
| Ireland |
| Italy |
| Poland |
| Portugal |
| Spain |
| Sweden |
| Türkiye |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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