| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced/metastatic melanoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with advanced/metastatic Skin cancer (melanoma) will particiate in this study |
|
| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10053571 |
| E.1.2 | Term | Melanoma |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 objective response rate (ORR) of participants treated with intravenous (IV) V937 administered in combination with pembrolizumab (MK-3475), intratumoral (ITu) V937 administered in
combination with pembrolizumab, or pembrolizumab alone per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by blinded independent central review (BICR) |
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate progression free survival (PFS), and duration of response (DOR) of participants treated with IV V937 in combination with pembrolizumab, ITu V937 in combination with pembrolizumab, or
pembrolizumab alone per RECIST 1.1 by BICR
2. To evaluate ORR, PFS, and DOR of participants treated with IV V937 in combination with pembrolizumab, ITu V937 in combination with pembrolizumab, or pembrolizumab alone, per RECIST 1.1, as assessed by the investigator
3. To evaluate overall survival (OS) of participants treated with IV V937 in combination with pembrolizumab, ITu V937 in combination with pembrolizumab, or pembrolizumab alone
4. To assess the safety and tolerability of participants treated with IV V937 in combination with pembrolizumab, ITu V937 in combination with pembrolizumab, or pembrolizumab alone |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Has histologically or cytologically confirmed diagnosis of advanced/metastatic melanoma
2. Has Stage III (unresectable) or Stage IV melanoma
3. Participants must be naive to anti-PD-(L)1 treatment, TVEC and other oncolytic viruses
4. Has 2 lesions as defined below:
Lesion 1: Has at least 1 cutaneous or subcutaneous lesion amenable to IT injection and biopsy. The injectable lesion must be measurable and meet 1 of the following criteria (per RECIST 1.1 for solid tumors):
- A cutaneous or subcutaneous lesion ≥ 1 cm in longest diameter for solid tumors, or ≥ 1.5 cm in short axis for a nodal lesion in participants with solid tumor. The longest diameter for an injectable lesion must be ≤ 10 cm for both solid tumors and nodal lesions in participants with solid tumor
- Multiple coalescing, superficial lesions that in aggregate have a longest diameter of ≥ 1 cm and ≤ 10 cm
Lesion 2: Have at least 1 measurable, distant and/or discrete noninjected lesion that is amenable to biopsy via visual inspection or amenable to biopsy via image guidance, such as ultrasound or computed tomography (CT)/magnetic resonance imaging (MRI). The lesion must be measurable and meet 1 of the above mentioned criteria per RECIST 1.1
5. Has a a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale
6. Demonstrates adequate organ function
7. Is male or female, from ≥18 years of age, at the time of signing the informed consent
8. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 120 days:
- Refrain from donating sperm
PLUS either:
- Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent
OR
- Must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause) as detailed below:
Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant
9. 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 woman of childbearing potential (WOCBP)
OR
- Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), 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 120 days after the last dose of study intervention. The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention
- A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 72 hours before the first dose of study intervention
- If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive
- The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy
10. The participant (or legally acceptable representative if applicable) provides written informed consent for the study. The participant must consent to screening and on-treatment biopsies. The participant may also provide consent for future biomedical research (FBR). However, the participant may participate in the main study without participating in FBR
11. Has measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions
12. Is able to provide newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides
13. HIV-infected participants must have well controlled HIV on antiretroviral therapy (ART) |
|
| E.4 | Principal exclusion criteria |
1.Has had chemotherapy, definitive radiation, or biological cancer therapy or an investigational agent or investigational device within 4 weeks (2 weeks for palliative radiation) prior to the first dose of study intervention or has not recovered to Common Terminology Criteria for Adverse Events Grade 1 or better (except alopecia) from any AEs that were due to cancer therapeutics administered more than 4 weeks earlier. If participant received major surgery or radiation therapy of>30 Gy, they must have recovered from the toxicity and/or complications from the intervention. Participants receiving ongoing replacement hormone therapy for endocrine immune-related AEs will not be excluded from participation in this study
2.Has ocular melanoma
3.Has radiographic evidence of major blood vessel invasion/infiltration. The degree of tumor invasion/infiltration of major blood vessels should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis
4.Has clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study drug
5.Has an active autoimmune disease that has required systemic treatment in the past 2 years except vitiligo or resolved childhood asthma/atopy. Replacement therapy, such as thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, is not considered a form of systemic treatment and is allowed
6.HIV-infected participants with a history of Kaposi’s sarcoma and/or Multicentric Castleman’s Disease
7.Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study
8.Has undergone prior allogeneic hematopoietic stem cell transplantation within the last 5 years
9. Has not fully recovered from any effects of major surgery without significant detectable infection. Surgeries that required general anesthesia must be completed at least 2 weeks before first study intervention administration. Surgery requiring regional/epidural anesthesia must be completed at least 72 hours before first study intervention administration and participants should be recovered
10.Clinically significant cardiovascular disease:cerebral vascular accident/stroke (<6 months prior to enrollment), myocardial infarction (<6 months prior to enrollment), unstable angina, congestive heart failure, or serious cardiac arrhythmia requiring medication
11.A woman of childbearing potential who has a positive urine pregnancy test within 72 hours prior to randomization or treatment allocation. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
12.Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor
13.Has received a live vaccine within 30 days prior to the first dose of study drug. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines are live attenuated vaccines and are not allowed
14.Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention
15.Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy in excess of replacement doses or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug. Use of nonsystemic steroids is permitted
16.Has a known additional malignancy that is progressing or has required active treatment within the past 2 years
17.Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, for at least 4 weeks by repeat imaging, clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention
18.Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients
19.Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
20.Has an active infection requiring systemic therapy
21.Has a known history of Hepatitis B or known active Hepatitis C virus infection
22.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
23.Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study intervention
24.Has had an allogenic tissue/solid organ transplant |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1. Objective Response Rate (ORR) per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Progression-free Survival (PFS) per RECIST 1.1 as Assessed by BICR
2. Duration of Response (DOR) per RECIST 1.1 as Assessed by BICR
3. ORR per RECIST 1.1 as Assessed by the Investigator
4. PFS per RECIST 1.1 as Assessed by the Investigator
5. DOR per RECIST 1.1 as Assessed by the Investigator
6. Overall Survival (OS)
7. Number of Participants with One or More Adverse Events (AEs)
8.Number of Participants who Discontinue Study Drug Due to an AE
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to 3 years
2. Up to 3 years
3. Up to 3 years
4. Up to 3 years
5. Up to 3 years
6. Up to 3 years
7. Up to 30 days after last dose (up to 3 years)
8. Up to 2 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 | Yes |
| 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 | No |
| 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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 21 |
| 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 |
| Australia |
| Israel |
| Korea, Republic of |
| New Zealand |
| South Africa |
| United States |
| France |
| Spain |
| Germany |
| Italy |
| Norway |
| 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
|
The overall study ends when the last participant completes the last
study-related telephone-call or visit, withdraws from the study, or is
lost to follow-up (ie, the participant is unable to be contacted by the
investigator).
For purposes of analysis and reporting, the overall study
ends when the Sponsor receives the last laboratory test result or at the time of final contact with the last participant, whichever comes last. |
|
| 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 | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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