Clinical trial NCT03875079: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Metastatic Melanoma
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2019-03-14
Enrollment: 83
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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).

Primary outcomes:
measure: Percentage of participants with adverse events
timeFrame: Baseline to end of study (approximately 24 months)
Secondary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: 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)
timeFrame: Baseline to end of study (approximately 24 months)
measure: Disease Control Rate (DCR)
timeFrame: Baseline to end of study (approximately 24 months)
measure: Duration of Response
timeFrame: 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)
timeFrame: 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
timeFrame: Baseline to end of study (approximately 24 months)
measure: Fibroblast Activation Protein-a (FAP)
timeFrame: 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
timeFrame: Baseline to end of study (approximately 24 months)
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Boston
country: United States
facility: Beth Israel Deaconess Med Ctr
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: North Sydney
country: Australia
facility: Melanoma Institute Australia
state: New South Wales
city: Melbourne
country: Australia
facility: Peter Maccallum Cancer Institute; Clinical Trial Unit
state: Victoria
city: Edegem
country: Belgium
facility: UZ Antwerpen
city: Leuven
country: Belgium
facility: UZ Leuven Gasthuisberg
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre
state: Ontario
city: Montreal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Lille
country: France
facility: Hopital Claude Huriez; Sce Dermatologie
city: Marseille
country: France
facility: Hôpital de la Timone; Dermatologie
city: Rennes
country: France
facility: Centre Eugene Marquis; Service d'oncologie
city: Villejuif
country: France
facility: Institut Gustave Roussy; Dermatologie
city: Moscow
country: Russian Federation
facility: Main Military Clinical Hospital named after N.N. Burdenko
state: Moskovskaja Oblast
city: Moscow
country: Russian Federation
facility: Russian Oncology Research Center n.a. N.N. Blokhin
city: Moscow
country: Russian Federation
facility: P.A. Gertsen Cancer Research Inst. ; Chemotherapy Dept
city: Saint-Petersburg
country: Russian Federation
facility: FBI "Scientific Research Institute of Oncology n. a. N. N. Petrov"
city: Pamplona
country: Spain
facility: Clinica Universitaria de Navarra; Servicio de Oncologia
state: Navarra
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron; Oncology
city: Barcelona
country: Spain
facility: Hospital Clínic i Provincial; Servicio de Oncología
city: Madrid
country: Spain
facility: Clinica Universidad de Navarra Madrid; Servicio de Oncología
city: Madrid
country: Spain
facility: Hospital Ramon y Cajal; Servicio de Oncologia
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: