| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Diffuse Large B-cell Lymphoma (DLBCL) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Phase II dose confirmation study in diffuse large B-cell lymphoma |
|
| 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 the safety and tolerability and to establish a RP2D of zilovertamab vedotin when used in combination with R-CHP.
2. To evaluate zilovertamab vedotin at the RP2D in combination with R-CHP with respect to complete response rate per Lugano response as assessed by the investigator. |
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate zilovertamab vedotin at the RP2D in combination with R-CHP with respect to ORR per Lugano response criteria as assessed by the investigator.
2. To evaluate zilovertamab vedotin at the RP2D in combination with R-CHP with respect to DOR per Lugano response criteria as assessed by the investigator. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histologically confirmed diagnosis of DLBCL, by prior biopsy, according to the WHO classification of neoplasms of the hematopoietic and lymphoid tissues, which includes but is not limited to: 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 overexpression 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.
Sites are required to collect DLBCL classification of BCL2, BCL6, MYC, ABC, and GCB status.
Sites should preform test locally and when not available, will be done centrally. The results are not required prior to C1D1.
2. Has PET-positive disease verified by BICR at Screening, defined as 4-5 on the Lugano 5-point scale.
3. Has received no prior treatment for their DLBCL.
4. Is assigned male or female sex at birth or an individual of any sex or gender ≥ 18 years old at the time of providing documented
informed consent.
5. If capable of producing sperm, the participant, agrees to the following during the intervention period and for at least the time needed to
eliminate 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
- Cyclophosphamide: 90 days
- Doxorubicin: 90 days
- Rituximab or rituximab biosimilar (Truxima): no contraception needed
• Refrains from donating sperm
PLUS either:
• Abstains from penile-vaginal intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agrees to remain abstinent
OR
• Uses contraception unless confirmed to be azoospermic as below:
- Uses a penile/external condom when having penile-vaginal intercourse with nonparticipant of childbearing potential who is not currently pregnant. PLUS partner use of an additional contraceptive method, as a condom may break or leak.
- Contraceptive use by participants capable of producing sperm should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions are more stringent than the requirements above, the local label requirements are to be followed.
6. A participant assigned female sex at birth is eligible to participate if not pregnant or breastfeeding, and at least one of the following conditions applies:
• Not a POCBP
OR
• POCBP and:
- Uses a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or be abstinent from penile-vaginal intercourse as their preferred and usual lifestyle, as described in Appendix 5 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 to others or freeze/store eggs during this
period for the purpose of reproduction. The length of time required to continue contraception for each study intervention is as follows:
. Zilovertamab vedotin: 50 days
. Cyclophosphamide: 180 days
. Doxorubicin: 180 days
. Rituximab or rituximab biosimilar (Truxima): 365 days
The investigator should evaluate the potential for contraceptive method failure in relationship to the first dose of study intervention. Contraceptive use by POCBPs should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions is more stringent than the requirements above, the local label equirements are to be followed.
- Has a negative highly sensitive pregnancy test 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 175 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 POCBPs with an early undetected pregnancy.
7. 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.
8. Have an ECOG performance status of 0 to 1 assessed within 7 days prior to start of C1D1.
9. Have adequate organ function as def in Table 3. Specimens must be collected within 7 days before the start of the study interv. |
|
| E.4 | Principal exclusion criteria |
1. Has a history of transformation of indolent disease to DLBCL.
2. Has received solid organ transplant at any time.
3. Has received a diagnosis of PMBCL.
4. 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), or serious cardiac arrhythmia requiring medication.
5. Has pericardial effusion or clinically significant pleural effusion.
6. Has ongoing Grade >1 peripheral neuropathy.
7. Has a demyelinating form of Charcot-Marie-Tooth disease.
8. History of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years.
9. Has contraindication to any of the study intervention components.
10. Has received prior radiotherapy within 28 days of start of study intervention. Participants must have recovered from all radiation-related toxicities.
11. Has ongoing corticosteroid therapy (exceeding 30 mg daily of prednisone equivalent). Prednisone equivalent dosing must have been stable for at least 28 days prior to C1D1.
12. Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed.
13. 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 until < 30 days after the last dose (see Section 6.5.2).
14. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 28 days before the first dose of study intervention.
15. Has known active CNS lymphoma. Participants with prior CNS involvement are eligible if their CNS disease is in radiographic, cytological (for cerebrospinal fluid disease), and clinical remission.
16. Has an active infection requiring systemic therapy.
17. Has a known history of HIV infection.
18. Has a known active hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
19. Has a known active hepatitis B infection defined as positive HBsAg and negative HBcAb or detectable HBV DNA by PCR testing.
20. 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.
21. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Number of Participants Who Experienced Dose-limiting Toxicities (DLTs) in Cycle 1
2. Number of Participants Who Experienced At Least One Adverse Event (AE)
3. Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)
4. Complete Response Rate (CRR) per Lugano Response Criteria |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Cycle 1 (up to 21 days)
2. Up to approximately 42 months
3. Up to approximately 5.5 months
4. Up to approximately 42 months |
|
| E.5.2 | Secondary end point(s) |
1. Objective Response Rate (ORR) per Lugano Response Criteria
2. Duration of Response (DOR) per Lugano Response Criteria |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 42 months
2. Up to approximately 42 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 | Yes |
| 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 |
| anti-drug Antibody and total 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| 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 |
| Israel |
| Korea, Republic of |
| Poland |
| Spain |
| Italy |
| Russian Federation |
| Turkey |
|
| 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
|
|
| 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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