| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of participants with Relapsed or Refractory Diffuse Large B-Cell Lymphoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Diffuse Large B Cell Lymphoma (a type of non-Hodgkin’s lymphoma, in patients who failed prior therapies) |
|
| 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 | PT |
| E.1.2 | Classification code | 10012818 |
| E.1.2 | Term | Diffuse large B-cell lymphoma |
| 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 zilovertamab vedotin with respect to objective response rate per Lugano Response Criteria as assessed by Blinded Independent Central Review (BICR) |
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate zilovertamab vedotin with respect to duration of response per Lugano Response Criteria as assessed by BICR
2. To evaluate the safety and tolerability of zilovertamab vedotin
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Has relapsed or refractory DLBCL, has progressed after at least 2 lines of prior therapy, and has progressed after auto-SCT or is auto-SCT ineligible. Must have received prior multiagent regimen that includes an alkylating agent, anthracycline, and anti-CD20 monoclonal antibody
a Relapsed disease: progression (Lugano) ≥6 months from completion of the most recent therapy after achieving an overall response of PR or CR
b Refractory disease: failure to achieve CR or PR to the most recent therapy OR disease progression (Lugano) <6 months from completion of the most recent therapy after achieving an overall response of PR or CR
c Ineligibility for auto-SCT:
Is >65 years old
Has organ dysfunction or comorbidities precluding the use of HDT orauto-SCT
Has not responded to salvage therapy
Has refused auto-SCT
Has an inability to successfully collect peripheral blood stem cells
2. Histologically confirmed diagnosis of DLBCL, according to the WHO classification of neoplasms of the hematopoietic and lymphoid tissues, including: DLBCL, NOS, germinal center B-cell type, or activated B-cell type; DLBCL leg-type; EBV+ DLBCL, NOS; and T cell histiocytic-rich DLBCL DLBCL with over-expression of MYC, BCL2, and/or BCL6 proteins without rearrangement are also classified as DLBCL. DLBCL (HGBL) with MYC, BCL2, and/or BCL6 rearrangement will also be included
3. a. Has radiographically measurable DLBCL per the Lugano Response Criteria, with at least 1 nodal lesion (non-irradiated) that is >1.5 cm in the long axis, regardless of length of the short axis, AND/OR extranodal lesion of ≥1.0 cm in the long and short axis and
b. Has PET positive disease verified by BICR at Screening defined as 4-5 on a 5-point scale
4. Has post-CAR-T cell therapy failure or is ineligible for CAR-T cell therapy
5. Life expectancy of at least 3 months, in the opinion of the investigator
6. Is male or female, from 18 years of age inclusive, at the time of signing the informed consent
7. Male participants are eligible to participate if they agree 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:
• Zilovertamab vedotin: 110 days
• Refrain from donating sperm
PLUS either:
• Be abstinent from heterosexual intercourse as their preferred and
usual lifestyle and agree to remain abstinent
OR
• Must agree to use contraception unless confirmed to be azoospermic
• Contraceptive use by men should be consistent with local regulations
8. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
• Is not a WOCBP
OR
• Is 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 (abstinent on a long-term and persistent basis), during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period. The length of time required to continue contraception for each study intervention is as follows:
◦ Zilovertamab Vedotin 50 days
The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention
-Contraceptive use by women should be consistent with local regulations
- Has a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours for urine and 72 hours for serum before the first dose of study intervention. If a urine test cannot be confirmed as negative, a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive
- Abstains from breastfeeding during the study intervention period and for at least 20 days after study intervention zilovertamab vedotin
- Has had her medical history, menstrual history, and recent sexual activity reviewed by the investigator to decrease the risk for inclusion of a woman with an early undetected pregnancy
9. The participant (or legally acceptable representative) has provided documented informed consent/assent for the study. The participant may also provide consent/assent for FBR
However, the participant may participate in the study without participating in FBR
10. Archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated has been provided
11. Has an ECOG performance status of 0 to 2 assessed within 7 days prior to start of C1D1. ECOG 2 will be capped at 20% per cochort
12. Has an adequate organ function |
|
| E.4 | Principal exclusion criteria |
1. Has received a diagnosis of PMBCL.
2. Has undergone solid organ transplant at any time.
3. 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, congestive heart failure (New York Heart Association Classification Class ≥ II), serious cardiac arrhythmia requiring medication, arterial
thromboembolism, cerebrovascular thromboembolism (<6 months prior to enrollment), uncontrolled Grade ≥3 hypertension (diastolic blood pressure ≥100 mm Hg or systolic blood pressure ≥160 mm Hg) despite antihypertensive therapy; or significant conduction system ECG
abnormalities, including second-degree AV block type II, third-degree AV block, or Grade ≥2 bradycardia, or serious cardiac arrhythmia requiring medication.
4. Known history of liver cirrhosis.
5. Has pericardial effusion or clinically significant pleural effusion.
6. Has baseline peripheral neuropathy> Grade 1.
7. Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years.
8. Has a demyelinating form of Charcot-Marie-Tooth disease.
9. Transformed DLBCL from indolent lymphoma.
10. 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.
11. Has received prior therapy with a ROR1-directed therapy.
12. Has contraindication to any of the study intervention components.
13. Has received prior systemic anticancer therapy, including investigational agents within 4 weeks prior to the first dose of study intervention.
14. Has received prior radiotherapy within 28 days of start of study intervention. Participants must have recovered from all radiation-related toxicities.
15. Has ongoing corticosteroid therapy (exceeding 30 mg daily of prednisone equivalent). Prednisone equivalent dosing must have been stable for at least 4 weeks prior to C1D1.
16. Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed.
17. 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 Cycle 1 of study therapy
18. 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.
19. 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.
20. Has an active infection requiring systemic therapy.
21. Has a known history of HIV infection. No HIV testing is required unless mandated by local health authority.
22. Has a known history of hepatitis B (defined as HBsAg reactive) or known active hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
23. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
24. Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study.
Meals and Dietary Restrictions:
Participants should avoid ingestion of grapefruit, grapefruit juice, Seville oranges, or starfruit (all of which contain CYP3A4 inhibitors) and should not use St. John's wort (which is a potent CYP3A4 inducer).
Otherwise, participants should maintain a normal diet unless modifications are required to manage an AE such as diarrhea, nausea, or vomiting. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1. Objective Response Rate (ORR) per Lugano Response Criteria |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1. Up to approximately 3.5 years |
|
| E.5.2 | Secondary end point(s) |
1. Duration of Response (DOR) per Lugano Response Criteria
2. Number of Participants Who Experience an Adverse Event (AE)
3. Number of Participants Who Discontinue Study Treatment Due to an AE |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 3.5 years
2. Up to approximately 3.5 years
3. Up to approximately 3.5 years
|
|
| 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 |
|
| 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.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 50 |
| 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 |
| Argentina |
| Canada |
| Chile |
| Israel |
| Korea, Republic of |
| Puerto Rico |
| South Africa |
| Thailand |
| United States |
| Estonia |
| France |
| Poland |
| Sweden |
| Spain |
| Switzerland |
| Czechia |
| Germany |
| Greece |
| Italy |
| Ireland |
| Norway |
| Russian Federation |
| Turkey |
| Ukraine |
| United Kingdom |
|
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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