A Study to Evaluate the Safety and Tolerability of RO7296682 in Participants With Advanced Solid Tumors

Phase 1

Terminated

• Conditions: Solid Tumors
• Interventions: Drug: RO7296682

• Registration Number: NCT04158583
• Lead Sponsor: Hoffmann-La Roche

Brief Summary

This study was planned to evaluate the safety and tolerability of RO7296682 in participants with advanced solid tumors.

Detailed Description

A Phase 1, open-label, dose-escalation study designed to evaluate the safety and tolerability of RO7296682 in participants with advanced and/or metastatic solid tumors. RO7296682 was administered by IV infusion Q3W. This entry-into-human study is divided into a dose-escalation stage (Part A) and a dose expansion stage (Part B).

Study Timeline

• Study First Submitted: 2019-11-05
• Study First Submitted QC: 2019-11-07
• Study First Posted: 2019-11-12
• Study Start: 2019-12-09
• Primary Completion: 2022-07-21
• Study Completion: 2022-07-21
• Status Verified: 2023-07
• Results First Submitted: 2023-07-19
• Results First Submitted QC: 2023-07-19
• Last Update Submitted: 2023-07-19
• Results First Posted: 2024-03-04
• Last Update Posted: 2024-03-04

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 76

Inclusion Criteria

1. Diagnosis of advanced and/or metastatic solid tumors who have progressed on all standard therapies, are intolerant to Standard-Of-Care (SOC), and/or are non-amenable to SOC. Participants whose tumors have known sensitizing mutation must have experienced disease progression (during or after treatment) or intolerance to treatment with a respective targeted therapy.
2. Measurable disease according to response evaluation criteria in solid tumors (RECIST) v1.1.
3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
4. Able to provide the most recent archival tumor tissue samples.
5. Adequate cardiovascular, haematological, liver and renal function.
6. Participants on therapeutic anticoagulation must be on a stable anticoagulant regimen.
7. Women of Childbearing Potential: Agreement to remain abstinent (refrain from heterosexual intercourse) or use highly effective contraceptive methods.
8. Men: Agreement to remain abstinent (refrain from heterosexual intercourse) or use highly effective contraceptive methods and refrain from donating sperm.

Exclusion Criteria

1. Pregnancy, lactation, or breastfeeding.
2. Known hypersensitivity to any of the components of RO7296682, including but not limited to hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanized antibodies.
3. History or clinical evidence of central nervous system (CNS) primary tumors or metastases.
4. Participants with another invasive malignancy in the last two years.
5. Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results.
6. Participants with known active or uncontrolled infection.
7. Positive human immunodeficiency virus (HIV) test at screening.
8. Positive for Hepatitis B and C.
9. Vaccination with live vaccines within 28 days prior to C1D1.
10. Major surgical procedure or significant traumatic injury within 28 days prior to first RO7296682 infusion.
11. Participants with wound healing complications.
12. Dementia or altered mental status that would prohibit informed consent.
13. History of Stevens-Johnson syndrome, toxic epidermal necrolysis, or DRESS (drug rash with eosinophilia and systemic symptoms).
14. Active or history of autoimmune disease or immune deficiency.
15. Prior treatment with checkpoint inhibitors (CPIs) (e.g. anti-CTLA4, anti-PD1, anti-PDL1), immunomodulatory monoclonal antibodies (mAbs) and/or mAb-derived therapies (approved or investigational) is approved.
16. Prior treatment with a CC chemokine receptor 4 (CCR4)-targeting (e.g. mogamulizumab) or a CD25-targeting agent (e.g. basiliximab) is prohibited.
17. Treatment with standard radiotherapy, any chemotherapeutic agent, targeted therapy or treatment with any other investigational drug (defined as treatment for which there is currently no regulatory authority-approved indication) within 28 days or 5 half-lives of the drug (whichever is shorter), prior to the first RO7296882 administration on C1D1.
18. Radiotherapy within the last 4 weeks before start of study drug treatment, with the exception of limited palliative radiotherapy (for which no wash out period is required).

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Part A: Cohort 1 RO7296682 0.3 mg Q3W	RO7296682	Participants with non-small cell lung cancer (NSCLC), melanoma (MEL), head and neck squamous cell carcinoma (HNSCC), ovarian cancer (OvC), triple-negative breast cancer (TNBC), and esophageal carcinoma (EsC) received RO7296682 0.3 milligram (mg) intravenous (IV) infusion on Day 1 of Cycle 1 (1 cycle=21 days), and at subsequent cycles, every 3 weeks (Q3W). Participants experiencing toxicities fulfilling the definition of a DLT (e.g: skin toxicities; Grade \>=4, IRR; Grade \>=4, immune-mediated adverse events; Grade \>=4) were discontinued from study treatment.
Part A: Cohort 2 RO7296682 1 mg Q3W	RO7296682	Participants with NSCLC, MEL, HNSCC, OvC, TNBC, and EsC received RO7296682 1 mg, IV infusion, on Day 1 of Cycle 1 (1 cycle=21 days), and at subsequent cycles, Q3W. Participants experiencing toxicities fulfilling the definition of a DLT (e.g: skin toxicities; Grade \>=4, IRR; Grade \>=4, immune-mediated adverse events; Grade \>=4) were discontinued from study treatment.
Part A: Cohort 5 RO7296682 18 mg Q3W	RO7296682	Participants with NSCLC, MEL, HNSCC, OvC, TNBC, and EsC received RO7296682 18 mg, IV infusion, on Day 1 of Cycle 1 (1 cycle=21 days), and at subsequent cycles, Q3W. Participants experiencing toxicities fulfilling the definition of a DLT (e.g: skin toxicities; Grade \>=4, IRR; Grade \>=4, immune-mediated adverse events; Grade \>=4) were discontinued from study treatment.
Part A: Cohort 6 RO7296682 35 mg Q3W	RO7296682	Participants with NSCLC, MEL, HNSCC, OvC, TNBC, and EsC received RO7296682 35 mg, IV infusion, on Day 1 of Cycle 1 (1 cycle=21 days), and at subsequent cycles, Q3W. Participants experiencing toxicities fulfilling the definition of a DLT (e.g: skin toxicities; Grade \>=4, IRR; Grade \>=4, immune-mediated adverse events; Grade \>=4) were discontinued from study treatment.
Part A: Cohort 7 RO7296682 70 mg Q3W	RO7296682	Participants with NSCLC, MEL, HNSCC, OvC, TNBC, and EsC received RO7296682 70 mg, IV infusion, on Day 1 of Cycle 1 (1 cycle=21 days), and at subsequent cycles, Q3W. Participants experiencing toxicities fulfilling the definition of a DLT (e.g: skin toxicities; Grade \>=4, IRR; Grade \>=4, immune-mediated adverse events; Grade \>=4) were discontinued from study treatment.
Part A: Cohort 8 RO7296682 100 mg Q3W	RO7296682	Participants with NSCLC, MEL, HNSCC, OvC, TNBC, and EsC received RO7296682 100 mg, IV infusion, on Day 1 of Cycle 1 (1 cycle=21 days), and at subsequent cycles, Q3W. Participants experiencing toxicities fulfilling the definition of a DLT (e.g: skin toxicities; Grade \>=4, IRR; Grade \>=4, immune-mediated adverse events; Grade \>=4) were discontinued from study treatment.
Part A: Cohort 3 RO7296682 2 mg Q3W	RO7296682	Participants with NSCLC, MEL, HNSCC, OvC, TNBC, and EsC received RO7296682 2 mg, IV infusion, on Day 1 of Cycle 1 (1 cycle=21 days), and at subsequent cycles, Q3W. Participants experiencing toxicities fulfilling the definition of a DLT (e.g: skin toxicities; Grade \>=4, IRR; Grade \>=4, immune-mediated adverse events; Grade \>=4) were discontinued from study treatment.
Part A: Cohort 4 RO7296682 6 mg Q3W	RO7296682	Participants with NSCLC, MEL, HNSCC, OvC, TNBC, and EsC received RO7296682 6 mg, IV infusion, on Day 1 of Cycle 1 (1 cycle=21 days), and at subsequent cycles, Q3W. Participants experiencing toxicities fulfilling the definition of a DLT (e.g: skin toxicities; Grade \>=4, IRR; Grade \>=4, immune-mediated adverse events; Grade \>=4) were discontinued from study treatment.
Part A: Cohort 9 RO7296682 165 mg Q3W	RO7296682	Participants with NSCLC, MEL, HNSCC, OvC, TNBC, and EsC received RO7296682 165 mg, IV infusion, on Day 1 of Cycle 1 (1 cycle=21 days), and at subsequent cycles, Q3W. Participants experiencing toxicities fulfilling the definition of a DLT (e.g: skin toxicities; Grade \>=4, IRR; Grade \>=4, immune-mediated adverse events; Grade \>=4) were discontinued from study treatment.
Part A: Cohort 10 RO7296682 20 mg Q3W	RO7296682	Participants with NSCLC, MEL, HNSCC, OvC, TNBC, and EsC received RO7296682 20 mg, IV infusion, on Day 1 of Cycle 1 (1 cycle=21 days), and at subsequent cycles, Q3W. Participants experiencing toxicities fulfilling the definition of a DLT (e.g: skin toxicities; Grade \>=4, IRR; Grade \>=4, immune-mediated adverse events; Grade \>=4) were discontinued from study treatment.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Adverse Events (AE) Determined According to The National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] v5.0)	From signing of informed consent form (ICF) until last follow-up visit (Up to approximately 2 years 7 months)	An adverse event (AE) is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product. An AE does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporarily associated with the use of a medicinal product, whether or not considered related to the medicinal product.
Number of Participants With Dose Limiting Toxicities (DLTs)	Up to 28 days	A DLT was defined as occurrence of a clinically significant adverse event (AE) from first administration of RO7296682 up to 7 days after second administration of RO7296682. DLTs were defined as following: 1) Hematologic toxicities - Grade 4 neutropenia lasting \>=7 days, Grade \>=3 febrile neutropenia, Grade 4 thrombocytopenia lasting \>=48 hours, Grade 3 thrombocytopenia associated with bleeding episode and Grade 4 anemia 2) Nonhematologic toxicities - Grade 3 nausea, vomiting or diarrhea, Grade \>=3 fatigue, Grade 3 arthralgia, fever \>40 degree Celsius occurs within 48 hours, Grade \>+ laboratory abnormalities, Grade 3 autoimmune thyroiditis or other endocrine abnormalities, Grade 3 tumor flare, Grade 3 transient increase of bilirubin in participants with liver lesions, transaminases (aspartate aminotransferase \[AST\]/alanine aminotransferase \[ALT\]) and/or gamma-glutamyl transferase (GGT) and any other RO7296682-related toxicity significant enough to be qualified as DLT.

Secondary Outcome Measures

Name	Time	Method
Maximum Serum Concentration (Cmax) of RO7296682	Cycles 1, and 3 or 4 (Cycle length = 21 days)
Volume of Distribution at Steady State (Vss) of RO7296682	Cycles 1, and 3 or 4 (Cycle length = 21 days)
Disease Control Rate (DCR)	From treatment initiation until last follow-up visit (Up to approximately 2 years 7 months)	DCR defined as the percentage of participants with an overall response of either CR, PR, or stable disease (SD), based on Investigators' assessment using RECIST Version 1.1. CR is defined as disappearance of all target lesions. any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. PD is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for (PD). PD is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study including baseline (nadir).
On-Treatment Progression Free Survival (PFS)	From treatment initiation until last follow-up visit (Up to approximately 2 years 7 months)	The PFS on treatment was defined as the time from study treatment initiation (Cycle 1 Day 1, (1 cycle=21 days) ) to the first occurrence of documented disease progression based on RECIST Version 1.1 Investigator's assessment, or death from any cause, whichever occurred first. For participants who did not have documented progressive disease or death (within 30 days from last study treatment) during the study, PFS was censored at the day of the last tumor assessment. Participants without any post baseline assessments or with all post-baseline assessments having unknown result/response but known to be alive at the clinical cut off for the analysis would be censored at the date of study treatment initiation plus one day.
Minimum Serum Concentration (Cmin) of RO7296682	Cycles 3 or 4 (Cycle length = 21 days)
Total Clearance (CL) of RO7296682	Cycles 1, and 3 or 4 (Cycle length = 21 days)
Terminal Half-Life (T1/2) of RO7296682	Cycles 1, and 3 or 4 (Cycle length = 21 days)
Treatment-induced Changes in Treg Levels in Blood and/or Tumor as Compared to Baseline	Baseline and at Cycle 1 Day 4 (Cycle length = 21 days)
Objective Response Rate (ORR)	From treatment initiation until last follow-up visit (Up to approximately 2 years 7 months )	ORR is defined as the percentage of participants having a complete response (CR) or partial response (PR) as determined by investigators' assessment of radiographic disease per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. CR is the disappearance of all target lesions and any pathological lymph nodes must have reduction in short axis to \< 10 millimeters (mm). PR is defined as at least a 30% decrease in the sum of diameters (SOD) of target lesions, taking as reference the Baseline sum diameters in the absence of CR.
Duration of Response (DOR)	From treatment initiation until last follow-up visit (Up to approximately 2 years 7 months)	DOR is defined as the time from first occurrence of a documented objective response to disease progression as determined by the investigator according to RECIST v1.1. or death from any cause, whichever occurs first. Objective response is defined as the percentage of participants having a CR or PR as determined by investigators' assessment of radiographic disease per RECIST v1.1. CR is the disappearance of all target lesions and any pathological lymph nodes must have reduction in short axis to \< 10 mm. PR is defined as at least a 30% decrease in the SOD of target lesions, taking as reference the Baseline sum diameters in the absence of CR.
Area Under the Serum Concentration Time Curve (AUC) of RO7296682	Cycles 1, and 3 or 4 (Cycle length = 21 days)
Treatment-induced Changes in Treg/Teff (T-regulatory Cell; T-effector Cell) Ratio in Blood and/or Tumor as Compared to Baseline	Baseline and at Cycle 1 Day 4 (Cycle length = 21 days)
Time of Maximum Concentration (Tmax) of RO7296682	Cycles 1, and 3 or 4 (Cycle length = 21 days)
Number of Participants With Anti-Drug Antibodies (ADA) During the Study Relative to the Prevalence of ADA at Baseline	Predose on Day 1 of each 21-day and subsequent cycles up to end of study (Up to approximately 2 years 7 months)

Trial Locations

Locations (11)

Cliniques Universitaires St-Luc; 🇧🇪 Bruxelles, Belgium

Princess Margaret Cancer Centre; 🇨🇦 Toronto, Ontario, Canada

The Ottawa Hospital Cancer Centre; 🇨🇦 Ottawa, Ontario, Canada

Rigshospitalet; Onkologisk Klinik; 🇩🇰 København Ø, Denmark

Vall d?Hebron Institute of Oncology (VHIO), Barcelona; 🇪🇸 Barcelona, Spain

Clinica Universitaria de Navarra; 🇪🇸 Pamplona, Navarra, Spain

START Madrid-FJD, Hospital Fundacion Jimenez Diaz; 🇪🇸 Madrid, Spain

START Madrid. Centro Integral Oncologico Clara Campal; CIOCC; 🇪🇸 Madrid, Spain

Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia; 🇪🇸 Valencia, Spain

Peter MacCallum Cancer Centre; Medical Oncology; 🇦🇺 Melbourne, Victoria, Australia

BC Cancer Agency - Vancouver; 🇨🇦 Vancouver, British Columbia, Canada