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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03875079
Recruitment Status : Recruiting
First Posted : March 14, 2019
Last Update Posted : October 9, 2020
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

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.

Condition or disease Intervention/treatment Phase
Metastatic Melanoma Drug: RO6874281 Drug: Pembrolizumab Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : June 24, 2019
Estimated Primary Completion Date : April 20, 2022
Estimated Study Completion Date : April 20, 2022

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Melanoma
MedlinePlus related topics: Melanoma

Arm Intervention/treatment
Experimental: Part I Safety Run in: RO6874281 + Pembrolizumab

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.

Drug: RO6874281

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.

Other Name: simlukafusp alfa

Drug: Pembrolizumab

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)


Experimental: Part II Expansion: RO6874281 + Pembrolizumab
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).
Drug: RO6874281

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.

Other Name: simlukafusp alfa

Drug: Pembrolizumab

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)


Experimental: Part III Expansion: RO6874281 + Pembrolizumab
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.
Drug: RO6874281

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.

Other Name: simlukafusp alfa

Drug: Pembrolizumab

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)





Primary Outcome Measures :
  1. Percentage of participants with adverse events [ Time Frame: Baseline to end of study (approximately 24 months) ]

Secondary Outcome Measures :
  1. 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) ]
  2. Complete Response Rate (CRR) [ Time Frame: Baseline to end of study (approximately 24 months) ]
  3. Disease Control Rate (DCR) [ Time Frame: Baseline to end of study (approximately 24 months) ]
  4. 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) ]
  5. 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) ]
  6. Baseline PD-L1 [ Time Frame: Baseline to end of study (approximately 24 months) ]
  7. Fibroblast Activation Protein-a (FAP) [ Time Frame: Baseline to end of study (approximately 24 months) ]
  8. 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) ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03875079


Contacts
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Contact: Reference Study ID Number: BP41054 www.roche.com/about_roche/roche_worldwide.htm 888-662-6728 (U.S. and Canada) global-roche-genentech-trials@gene.com

Locations
Show Show 23 study locations
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
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Study Director: Clinical Trials Hoffmann-La Roche
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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT03875079    
Other Study ID Numbers: BP41054
2018-003872-11 ( EudraCT Number )
First Posted: March 14, 2019    Key Record Dates
Last Update Posted: October 9, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan 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)."

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents