## Protocol Section
### Identification Module
**NCT ID:** NCT03875079

**Brief Title:** A Study To Evaluate Safety And Therapeutic Activity Of RO6874281 In Combination With Pembrolizumab, In Participants With Advanced Or Metastatic Melanoma

**Official Title:** An Open-Label, Multicenter, Phase Ib Study To Evaluate Safety And Therapeutic Activity Of RO6874281, An Immunocytokine, Consisting Of Interleukin-2 Variant (IL-2v) Targeting Fibroblast Activation Protein-Α (FAP), In Combination With Pembrolizumab (Anti-PD-1), In Participants With Advanced Or Metastatic Melanoma

#### Organization Study ID Info
**ID:** BP41054
#### Organization
**Class:** INDUSTRY
**Full Name:** Hoffmann-La Roche
#### Secondary ID Infos
**ID:** 2018-003872-11
**Type:** EUDRACT_NUMBER
### Status Module
#### Completion Date
**Date:** 2022-07-14

**Type:** ACTUAL

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2023-03-29

**Type:** ACTUAL

**Last Update Submit Date:** 2023-03-28

**Overall Status:** COMPLETED

#### Primary Completion Date
**Date:** 2022-07-14

**Type:** ACTUAL

#### Start Date
**Date:** 2019-06-24

**Type:** ACTUAL

**Status Verified Date:** 2023-03

#### Study First Post Date
**Date:** 2019-03-14
**Type:** ACTUAL
**Study First Submit Date:** 2019-03-13
**Study First Submit QC Date:** 2019-03-13
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** INDUSTRY

**Name:** Hoffmann-La Roche

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** True

### Description Module

**Brief Summary:** This is an open-label, multicenter, Phase Ib study to evaluate the safety and therapeutic activity of RO6874281 in combination with pembrolizumab. The study will consist of 3 parts: a safety run-in (Part I: Cohorts 1.1. and 1.2) and two expansion parts (Parts II and III). Part II will start once all participants in Cohort 1.1 have completed the observation period. Part III will start once all participants in Cohorts 1.1 and 1.2 have completed the observation period.

### Conditions Module

**Conditions:**

- Metastatic Melanoma

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** SINGLE_GROUP

##### Masking Info

**Masking:** NONE

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 83

**Type:** ACTUAL

**Phases:**

- PHASE1

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** Cohort 1.1 (CPI naive and experienced melanoma participants):

Participants will receive RO6874281 in combination with Pembrolizumab every 3 weeks (Q3W) and will be observed for 2 cycles (ie: 6 weeks) in order to confirm the safety of the proposed dose and schedule that will be used in Part II of this study.

Cohort 1.2 (CPI experienced melanoma participants only):

Participants will receive RO6874281 in combination with Pembrolizumab via an induction and maintenance schedule for RO6874281: QW three times (D1, D8, D15) followed by Q3W dosing (D22 and subsequent). Pembrolizumab is to be administered Q3W, starting on Day 1. Participants will be observed for 2 pembrolizumab cycles (ie: 6 weeks) in order to confirm the safety of the proposed dose and schedule that will be used in Part III of this study.

**Intervention Names:**

- Drug: RO6874281

- Drug: Pembrolizumab

**Label:** Part I Safety Run in: RO6874281 + Pembrolizumab

**Type:** EXPERIMENTAL

#### Arm Group 2

**Description:** Part II will start once all participants in Part I Cohort 1.1 have completed the observation period. Approximately 34 participants will receive RO6874281 in combination with Pembrolizumab every 3 weeks (Q3W) and will be observed for 2 cycles (ie: 6 weeks).

**Intervention Names:**

- Drug: RO6874281

- Drug: Pembrolizumab

**Label:** Part II Expansion: RO6874281 + Pembrolizumab

**Type:** EXPERIMENTAL

#### Arm Group 3

**Description:** Part III will start once all participants in Part I Cohorts 1.1 and 1.2 have completed the observation period. Approximately 80 participants will be randomised to receive RO6874281 in combination with Pembrolizumab in either a Q3W or QW/Q3W schedule.

**Intervention Names:**

- Drug: RO6874281

- Drug: Pembrolizumab

**Label:** Part III Expansion: RO6874281 + Pembrolizumab

**Type:** EXPERIMENTAL

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Part I Safety Run in: RO6874281 + Pembrolizumab

- Part II Expansion: RO6874281 + Pembrolizumab

- Part III Expansion: RO6874281 + Pembrolizumab

**Description:** Part I Safety Run in:

Cohort 1.1: RO6874281 will be administered by intravenous (IV) infusion; 10 mg (Q3W) every 3 weeks and will be observed over 2 administration cycles (i.e. 6 weeks) in order to confirm the safety of the proposed dose and schedule that will be used in Part II of this study.

Cohort 1.2: RO6874281 will be administered by IV infusion via an induction and maintenance phase; 10 mg (QW) every week for 3 weeks followed by 10 mg (Q3W) every 3 weeks and will be observed over 2 administration cycles (6 weeks) to confirm safety of the proposed dose and schedule to be used in Part III of this study.

Part II Expansion: RO6874281 will be administered by IV infusion; 10 mg (Q3W) every 3 weeks (or lower dose level depending on Part I Cohort 1.1 outcome).

Part III Expansion: RO6874281 will be administered by IV infusion; 10 mg (QW) every week or 10mg (Q3W) every 3 weeks (or lower dose level depending on Part I Cohorts 1.1 and 1.2 outcomes) in either a Q3W or QW/Q3W schedule.

**Name:** RO6874281

**Other Names:**

- simlukafusp alfa

**Type:** DRUG

#### Intervention 2

**Arm Group Labels:**

- Part I Safety Run in: RO6874281 + Pembrolizumab

- Part II Expansion: RO6874281 + Pembrolizumab

- Part III Expansion: RO6874281 + Pembrolizumab

**Description:** Part I Safety Run in (Cohorts 1.1 and 1.2): Pembrolizumab will be administered by IV; 200 mg Q3W and will be observed over 2 administration cycles (i.e. 6 weeks).

Part II Expansion: Pembrolizumab will be administered by IV; 200 mg Q3W (or lower dose level depending on Part I Cohort 1.1 outcome)

Part III Expansion: Pembrolizumab will be administered by IV; 200 mg Q3W (or lower dose level depending on Part I Cohorts 1.1 and 1.2 outcomes)

**Name:** Pembrolizumab

**Type:** DRUG

### Outcomes Module

#### Primary Outcomes

**Measure:** Percentage of participants with adverse events

**Time Frame:** Baseline to end of study (approximately 24 months)

#### Secondary Outcomes

**Measure:** Objective Response Rate (ORR)

**Time Frame:** Time from first occurrence of a documented objective response until the time of documented disease progression or death from any cause during treatment (whichever occurs first) until the end of study (approximately 24 months)

**Measure:** Complete Response Rate (CRR)

**Time Frame:** Baseline to end of study (approximately 24 months)

**Measure:** Disease Control Rate (DCR)

**Time Frame:** Baseline to end of study (approximately 24 months)

**Measure:** Duration of Response

**Time Frame:** Time from first occurrence of a documented objective response until the time of documented disease progression or death from any cause during treatment (whichever occurs first) until the end of study (approximately 24 months)

**Measure:** Progression Free Survival (PFS)

**Time Frame:** Time from study treatment initiation to the first occurrence of documented disease progression (based on Investigator's assessment) or death from any cause during treatment (whichever occurs first) until the end of study (approximately 24 months)

**Measure:** Baseline PD-L1

**Time Frame:** Baseline to end of study (approximately 24 months)

**Measure:** Fibroblast Activation Protein-a (FAP)

**Time Frame:** Baseline to end of study (approximately 24 months)

**Measure:** Change from baseline in density (cell/mm2) of immune cells including CD8+, FOXP3, and PD-L1

**Time Frame:** Baseline to end of study (approximately 24 months)

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

1. Histologically confirmed unresectable stage III or stage IV cutaneous or mucosal melanoma (AJCC v8.0).
2. Participants need to have known BRAF status.
3. CPI naïve melanoma population: Participants with unresectable stage III or stage IV cutaneous or mucosal melanoma who have not received prior treatment for advanced disease. BRAF mutation-positive patients are eligible without prior treatment or after failure of BRAF directed inhibitor therapy.
4. CPI experienced melanoma population: Participants with unresectable stage III or stage IV cutaneous melanoma. Participants must have progressed during or after treatment with anti PD-1 antibody therapy, either as monotherapy or in combination with other agent(s).
5. Participants should have adequate cardiovascular, hematological, liver, and renal function.
6. Participants with unilateral pleural effusion are eligible if they fulfill both of the following: NYHA Class 1; Forced expiratory volume 1 (FEV1) \>70% and forced vital capacity (FVC) \>70% of predicted value; participants with lung metastases should present with DLCO \>60% of predicted value.

Exclusion criteria:

Medical Conditions

1. Rapid disease progression or suspected hyperprogression (as determined by the Investigator) or threat to vital organs or critical anatomical sites requiring urgent alternative medical intervention.
2. Known active CNS metastases and/or carcinomatous meningitis/leptomeningeal disease:

   Participants with previously treated brain metastases may participate.
3. History of treated asymptomatic CNS metastases.
4. An active second malignancy (exceptions are non-melanoma skin cancer, cervical carcinoma in situ, or prostate carcinoma that is in remission under androgen deprivation therapy for ≥ 2 years, or participants who have a history of malignancy and have been treated with curative intent and the participant is expected to be cured as per Investigator's assessment).
5. Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results, and known autoimmune diseases or other disease with ongoing fibrosis (such as scleroderma, pulmonary fibrosis. and emphysema).
6. Episode of significant cardiovascular/cerebrovascular acute disease within 6 months before study treatment administration.
7. Active or uncontrolled infections, including latent tuberculosis.
8. Known HIV infection.
9. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
10. Severe infection within 4 weeks before study treatment administration, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia.
11. History of chronic liver disease or evidence of hepatic cirrhosis.
12. Dementia or altered mental status that would prohibit informed consent.
13. History of autoimmune disease.
14. Adverse events related to any previous radiotherapy, chemotherapy, targeted therapy, CPI therapy or surgical procedure that have not resolved to Grade =\< 1, except alopecia (any grade) and Grade 2 peripheral neuropathy.
15. History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest computed tomography (CT) scan.
16. Bilateral pleural effusion.
17. Severe dyspnea at rest or requiring supplementary oxygen therapy.
18. Concurrent therapy with any other investigational drug (defined as a treatment for which there is currently no regulatory authority approved indication).
19. Immunomodulating agents: Last dose with any of the following agents, for example, etanercept, infliximab, tacrolimus, cyclosporine, mycophenolic acid, alefacept, or efalizumab (or similar agents) \< 28 days before study treatment administration. Regular immunosuppressive therapy (i.e., for organ transplantation, chronic rheumatologic disease)
20. Treatment with systemic immunosuppressive medications including, but not limited to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF agents within 2 weeks prior to Cycle 1 Day 1.
21. Radiotherapy within the last 4 weeks before start of study treatment administration, with the exception of limited field palliative radiotherapy.
22. Administration of a live, attenuated vaccine within 4 weeks before Cycle 1 Day 1.
23. Major surgery or significant traumatic injury \< 28 days before study treatment administration (excluding fine needle biopsies) or anticipation of the need for major surgery during study treatment.
24. Known hypersensitivity to any of the components of the RO6874281 drug product or pembrolizumab drug product, including but not limited to hypersensitivity to Chinese Hamster Ovary cell products or other recombinant human or humanized antibodies.
25. No prior cytotoxic therapy for unresectable stage III or stage IV disease is permitted.
26. Toxicity from prior anti-PD-1 antibody therapy (including adjuvant treatment).

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Locations

**Location 1:**

**City:** New Haven

**Country:** United States

**Facility:** Yale University

**State:** Connecticut

**Zip:** 06510

**Location 2:**

**City:** Iowa City

**Country:** United States

**Facility:** University of Iowa

**State:** Iowa

**Zip:** 52242

**Location 3:**

**City:** Boston

**Country:** United States

**Facility:** Beth Israel Deaconess Med Ctr

**State:** Massachusetts

**Zip:** 02215

**Location 4:**

**City:** Boston

**Country:** United States

**Facility:** Dana Farber Cancer Institute

**State:** Massachusetts

**Zip:** 02215

**Location 5:**

**City:** North Sydney

**Country:** Australia

**Facility:** Melanoma Institute Australia

**State:** New South Wales

**Zip:** 2060

**Location 6:**

**City:** Melbourne

**Country:** Australia

**Facility:** Peter Maccallum Cancer Institute; Clinical Trial Unit

**State:** Victoria

**Zip:** 3000

**Location 7:**

**City:** Edegem

**Country:** Belgium

**Facility:** UZ Antwerpen

**Zip:** 2650

**Location 8:**

**City:** Leuven

**Country:** Belgium

**Facility:** UZ Leuven Gasthuisberg

**Zip:** 3000

**Location 9:**

**City:** Toronto

**Country:** Canada

**Facility:** Princess Margaret Cancer Centre

**State:** Ontario

**Zip:** M5G 1Z5

**Location 10:**

**City:** Montreal

**Country:** Canada

**Facility:** Jewish General Hospital

**State:** Quebec

**Zip:** H3T 1E2

**Location 11:**

**City:** Lille

**Country:** France

**Facility:** Hopital Claude Huriez; Sce Dermatologie

**Zip:** 59037

**Location 12:**

**City:** Marseille

**Country:** France

**Facility:** Hôpital de la Timone; Dermatologie

**Zip:** 13005

**Location 13:**

**City:** Rennes

**Country:** France

**Facility:** Centre Eugene Marquis; Service d'oncologie

**Zip:** 35042

**Location 14:**

**City:** Villejuif

**Country:** France

**Facility:** Institut Gustave Roussy; Dermatologie

**Zip:** 94805

**Location 15:**

**City:** Moscow

**Country:** Russian Federation

**Facility:** Main Military Clinical Hospital named after N.N. Burdenko

**State:** Moskovskaja Oblast

**Zip:** 105229

**Location 16:**

**City:** Moscow

**Country:** Russian Federation

**Facility:** Russian Oncology Research Center n.a. N.N. Blokhin

**Zip:** 115478

**Location 17:**

**City:** Moscow

**Country:** Russian Federation

**Facility:** P.A. Gertsen Cancer Research Inst. ; Chemotherapy Dept

**Zip:** 125284

**Location 18:**

**City:** Saint-Petersburg

**Country:** Russian Federation

**Facility:** FBI "Scientific Research Institute of Oncology n. a. N. N. Petrov"

**Location 19:**

**City:** Pamplona

**Country:** Spain

**Facility:** Clinica Universitaria de Navarra; Servicio de Oncologia

**State:** Navarra

**Zip:** 31008

**Location 20:**

**City:** Barcelona

**Country:** Spain

**Facility:** Hospital Universitari Vall d'Hebron; Oncology

**Zip:** 08035

**Location 21:**

**City:** Barcelona

**Country:** Spain

**Facility:** Hospital Clínic i Provincial; Servicio de Oncología

**Zip:** 08036

**Location 22:**

**City:** Madrid

**Country:** Spain

**Facility:** Clinica Universidad de Navarra Madrid; Servicio de Oncología

**Zip:** 28027

**Location 23:**

**City:** Madrid

**Country:** Spain

**Facility:** Hospital Ramon y Cajal; Servicio de Oncologia

**Zip:** 28034

#### Overall Officials

**Official 1:**

**Affiliation:** Hoffmann-La Roche

**Name:** Clinical Trials

**Role:** STUDY_DIRECTOR

### IPD Sharing Statement Module

**Description:** "Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.clinicalstudydatarequest.com). Further details on Roche's criteria for eligible studies are available here (https://clinicalstudydatarequest.com/Study-Sponsors/Study-Sponsors-Roche.aspx). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm)."

**IPD Sharing:** NO

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000018358

- Term: Neuroendocrine Tumors

- ID: D000017599

- Term: Neuroectodermal Tumors

- ID: D000009373

- Term: Neoplasms, Germ Cell and Embryonal

- ID: D000009370

- Term: Neoplasms by Histologic Type

- ID: D000009369

- Term: Neoplasms

- ID: D000009380

- Term: Neoplasms, Nerve Tissue

- ID: D000018326

- Term: Nevi and Melanomas

- ID: D000012878

- Term: Skin Neoplasms

- ID: D000009371

- Term: Neoplasms by Site

- ID: D000012871

- Term: Skin Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BC04

- Name: Neoplasms

- Abbrev: BC17

- Name: Skin and Connective Tissue Diseases

- Abbrev: All

- Name: All Conditions

- Abbrev: Rare

- Name: Rare Diseases

### Condition Browse Module - Browse Leaves

- ID: M11528

- Name: Melanoma

- Relevance: HIGH

- As Found: Melanoma

- ID: M20495

- Name: Neuroendocrine Tumors

- Relevance: LOW

- As Found: Unknown

- ID: M19845

- Name: Neuroectodermal Tumors

- Relevance: LOW

- As Found: Unknown

- ID: M20388

- Name: Neuroectodermal Tumors, Primitive

- Relevance: LOW

- As Found: Unknown

- ID: M12318

- Name: Neoplasms, Germ Cell and Embryonal

- Relevance: LOW

- As Found: Unknown

- ID: M12315

- Name: Neoplasms by Histologic Type

- Relevance: LOW

- As Found: Unknown

- ID: M12325

- Name: Neoplasms, Nerve Tissue

- Relevance: LOW

- As Found: Unknown

- ID: M12448

- Name: Nevus, Pigmented

- Relevance: LOW

- As Found: Unknown

- ID: M12446

- Name: Nevus

- Relevance: LOW

- As Found: Unknown

- ID: M20470

- Name: Nevi and Melanomas

- Relevance: LOW

- As Found: Unknown

- ID: M15681

- Name: Skin Neoplasms

- Relevance: LOW

- As Found: Unknown

- ID: M15674

- Name: Skin Diseases

- Relevance: LOW

- As Found: Unknown

- ID: T4091

- Name: Neuroendocrine Tumor

- Relevance: LOW

- As Found: Unknown

- ID: T4092

- Name: Neuroepithelioma

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000008545

- Term: Melanoma

### Intervention Browse Module - Ancestors

- ID: D000074322

- Term: Antineoplastic Agents, Immunological

- ID: D000000970

- Term: Antineoplastic Agents

- ID: D000082082

- Term: Immune Checkpoint Inhibitors

- ID: D000045504

- Term: Molecular Mechanisms of Pharmacological Action

### Intervention Browse Module - Browse Branches

- Abbrev: ANeo

- Name: Antineoplastic Agents

- Abbrev: All

- Name: All Drugs and Chemicals

- Abbrev: Analg

- Name: Analgesics

### Intervention Browse Module - Browse Leaves

- ID: M349416

- Name: Pembrolizumab

- Relevance: HIGH

- As Found: Blind

- ID: M10411

- Name: Interleukin-2

- Relevance: LOW

- As Found: Unknown

- ID: M1346

- Name: Antineoplastic Agents, Immunological

- Relevance: LOW

- As Found: Unknown

- ID: M2342

- Name: Immune Checkpoint Inhibitors

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: C000582435

- Term: Pembrolizumab

### Misc Info Module

- Version Holder: 2024-05-24
