A Study to Evaluate Safety, Pharmacokinetics, and Efficacy of RO6895882 in Participants With Advanced and/or Metastatic Solid Tumors

• ClinicalTrials.gov Identifier: NCT02004106
• Recruitment Status: Completed
• First Posted: December 6, 2013
• Last Update Posted: March 6, 2018
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Study Description

Brief Summary:

This open-label, multi-center, dose-escalation study will evaluate the safety, pharmacokinetics, and therapeutic activity of RO6895882 in participants with Carcinoembryonic Antigen (CEA)-positive solid tumors who have progressed on the standard of care therapy. The study will be conducted in 3 parts. Part 1 will be a single ascending dose study in single participant cohort at low RO6895882 dose (less than or equal to [</=] 6 milligrams [mg]). Part 2 will be a dose-escalation study of RO6895882 monotherapy given every week (qw), every 2 weeks (q2w), and possibly every 3 weeks (q3w). Part 3 will be an expansion phase of the qw, q2w, and possibly q3w at maximum tolerated dose (MTD) (as determined in Part 2). Part 3 will only be conducted if the risk/benefit assessment, as evaluated by the Sponsor and the investigators, is in favor of the participants. Participants will be treated until disease progression, unacceptable toxicity or withdrawal from treatment for other reasons or death for a maximum duration of 24 months.

Condition or disease	Intervention/treatment	Phase
Neoplasms	Drug: RO6895882	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 110 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label, Multi-Center, Dose-Escalation, Phase I Study With an Expansion Phase, to Evaluate Safety, Pharmacokinetics and Therapeutic Activity of RO6895882, an Immunocytokine, Consisting of a Variant of Interleukin-2 (IL-2v) Targeting Carcinoembryonic Antigen (CEA) Administered Intravenously, in Patients With Advanced and/or Metastatic Solid Tumors
• Actual Study Start Date: December 31, 2013
• Actual Primary Completion Date: August 31, 2016
• Actual Study Completion Date: August 31, 2016

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part 1: RO6895882 Single Ascending Dose; Participants will receive RO6895882 at ascending doses (</= 6 mg) as a single intravenous (IV) infusion.	Drug: RO6895882; Participants will receive RO6895882 at different dose levels and schedules defined in respective arms as IV infusion.
Experimental: Part 2: RO6895882 Dose Escalation Monotherapy; Participants in different cohorts will receive RO6895882 at ascending doses as IV infusion qw, q2w or q3w. After completion of Part 2 all participants have the option to receive the recommended RO6895882 dose once defined in Part 2 at the discretion of investigator.	Drug: RO6895882; Participants will receive RO6895882 at different dose levels and schedules defined in respective arms as IV infusion.
Experimental: Part 3: RO6895882 MTD Expansion; Participants will receive RO6895882 at MTD determined in Part 2 as IV infusion qw, q2w or q3w.	Drug: RO6895882; Participants will receive RO6895882 at different dose levels and schedules defined in respective arms as IV infusion.

Outcome Measures

Primary Outcome Measures :

1. Part 2: Percentage of Participants With Dose-Limiting Toxicity (DLT) [ Time Frame: Part 2: within 21 days after the highest dose administration ]
2. Part 2: MTD of RO6895882 [ Time Frame: Part 2: within 21 days after the highest dose administration ]
3. Percentage of Participants With Adverse Events [ Time Frame: Day 1 up to 28 days after last dose of study drug (up to approximately 25 months) ]
4. Percentage of Participants With Anti-drug Antibodies (ADAs) Against RO6895882 [ Time Frame: Baseline up to 28-days after last dose (up to approximately 25 months) (please see outcome measure description for detailed time frame) ]
   Part 1: Predose (Hour [Hr] 0). Part 2/3: qw schedule (1 cycle = 1 week): Predose in Cycle 1, 4, 5, 6, thereafter every 2 months; Part 2/3: q2w schedule (1 cycle = 2 weeks): Predose in Cycle 1, 4, 6, thereafter every 8 weeks. Part 2/3: q3w schedule (1 cycle = 3 weeks): Predose in Cycle 1, 2, 3, 4, 6, thereafter every 9 weeks. Additionally at treatment discontinuation or at 28-days after last dose (up to approximately 25 months)
5. Area Under the Serum Concentration-Time Curve (AUC) of RO6895882 [ Time Frame: Baseline up to 28-days after last dose (up to approximately 25 months) (please see outcome measure description for detailed time frame) ]
   Predose (Hr 0), 1 hr post start of infusion (SoI), at end of infusion (EoI), 2, 4, 24, 72, 96, 216 hrs post Day 1 dose. Part 2/3: qw schedule (1 cycle = 1 week): Predose, 1 hr post SoI, at EoI, 2, 4 hrs after EoI, 24, 72, 96 hrs postdose in Cycle 1, 5 (include 120 hrs postdose); Predose, 24, 96 hrs postdose in Cycle 2, 3, 4; Predose in any later cycle. Part 2/3: q2w schedule (1 cycle = 2 weeks): Predose, 1 hr post SoI, at EoI, 2, 4, 24, 72, 96, 120, 168, 312 hrs postdose in Cycle 1, 4 (exclude 312 hrs postdose); Predose, 24, 96, 168 hrs postdose in Cycle 2; Predose in all later cycles. Part 2/3: q3w schedule (1 cycle = 3 weeks): Predose, 1 hr post SoI, at EoI, 2, 4, 24, 72, 96, 120, 168, 312, 480 hrs postdose in Cycle 1; Predose, 24, 96, 312 hrs postdose in Cycle 2; Predose, at EoI, 1, 2, 4 hrs post EoI, 24, 72, 96, 120, 168, 312 hrs postdose in Cycle 3; Predose, 24, 72, 120, 312 hrs postdose in Cycle 4; Predose in all later cycles. Maximum infusion length = 2 hrs.
6. Minimum Observed Serum Concentration (Cmin) of RO6895882 [ Time Frame: Part 1/2/3: Predose (Hr 0) in all cycles (maximum up to 25 months) (cycle length = 1, 2, or 3 weeks, respectively) ]
7. Maximum Observed Serum Concentration (Cmax) of RO6895882 [ Time Frame: Baseline up to 28-days after last dose (up to approximately 25 months) (please see outcome measure description for detailed time frame) ]
   Part 1: Predose (Hr 0), 1 hr post SoI, at EoI, 2, 4, 24, 72, 96, 216 hrs post Day 1 dose. Part 2/3: qw schedule (1 Cycle = 1 week): Predose, 1 hr post SoI, at EoI, 2, 4 hrs after EoI, 24, 72, 96 hrs postdose in Cycle 1, 5 (include 120 hrs postdose); Predose, 24, 96 hrs postdose in Cycle 2, 3, 4; Predose in any later cycle. Part 2/3: q2w schedule (1 Cycle = 2 weeks): Predose, 1 hr post SoI, at EoI, 2, 4, 24, 72, 96, 120, 168, 312 hrs postdose in Cycle 1, 4 (exclude 312 hrs postdose); Predose, 24, 96, 168 hrs postdose in Cycle 2; Predose in all later cycles. Part 2/3: q3w schedule (1 Cycle = 3 weeks): Predose, 1 hr post SoI, at EoI, 2, 4, 24, 72, 96, 120, 168, 312, 480 hrs postdose in Cycle 1; Predose, 24, 96, 312 hrs postdose in Cycle 2; Predose, at EoI, 1, 2, 4 hrs post EoI, 24, 72, 96, 120, 168, 312 hrs postdose in Cycle 3; Predose, 24, 72, 120, 312 hrs postdose in Cycle 4; Predose in all later cycles. Maximum infusion length = 2 hrs.
8. Clearance (CL) of RO6895882 [ Time Frame: Baseline up to 28-days after last dose (up to approximately 25 months) (please see outcome measure description for detailed time frame) ]
   Part 1: Predose (Hr 0), 1 hr post SoI, at EoI, 2, 4, 24, 72, 96, 216 hrs post Day 1 dose. Part 2/3: qw schedule (1 Cycle = 1 week): Predose, 1 hr post SoI, at EoI, 2, 4 hrs after EoI, 24, 72, 96 hrs postdose in Cycle 1, 5 (include 120 hrs postdose); Predose, 24, 96 hrs postdose in Cycle 2, 3, 4; Predose in any later cycle. Part 2/3: q2w schedule (1 Cycle = 2 weeks): Predose, 1 hr post SoI, at EoI, 2, 4, 24, 72, 96, 120, 168, 312 hrs postdose in Cycle 1, 4 (exclude 312 hrs postdose); Predose, 24, 96, 168 hrs postdose in Cycle 2; Predose in all later cycles. Part 2/3: q3w schedule (1 Cycle = 3 weeks): Predose, 1 hr post SoI, at EoI, 2, 4, 24, 72, 96, 120, 168, 312, 480 hrs postdose in Cycle 1; Predose, 24, 96, 312 hrs postdose in Cycle 2; Predose, at EoI, 1, 2, 4 hrs post EoI, 24, 72, 96, 120, 168, 312 hrs postdose in Cycle 3; Predose, 24, 72, 120, 312 hrs postdose in Cycle 4; Predose in all later cycles. Maximum infusion length = 2 hrs.
9. Volume of Distribution at Steady State (Vss) of RO6895882 [ Time Frame: Baseline up to 28-days after last dose (up to approximately 25 months) (please see outcome measure description for detailed time frame) ]
   Part 1: Predose (Hr 0), 1 hr post SoI, at EoI, 2, 4, 24, 72, 96, 216 hrs post Day 1 dose. Part 2/3: qw schedule (1 Cycle = 1 week): Predose, 1 hr post SoI, at EoI, 2, 4 hrs after EoI, 24, 72, 96 hrs postdose in Cycle 1, 5 (include 120 hrs postdose); Predose, 24, 96 hrs postdose in Cycle 2, 3, 4; Predose in any later cycle. Part 2/3: q2w schedule (1 Cycle = 2 weeks): Predose, 1 hr post SoI, at EoI, 2, 4, 24, 72, 96, 120, 168, 312 hrs postdose in Cycle 1, 4 (exclude 312 hrs postdose); Predose, 24, 96, 168 hrs postdose in Cycle 2; Predose in all later cycles. Part 2/3: q3w schedule (1 Cycle = 3 weeks): Predose, 1 hr post SoI, at EoI, 2, 4, 24, 72, 96, 120, 168, 312, 480 hrs postdose in Cycle 1; Predose, 24, 96, 312 hrs postdose in Cycle 2; Predose, at EoI, 1, 2, 4 hrs post EoI, 24, 72, 96, 120, 168, 312 hrs postdose in Cycle 3; Predose, 24, 72, 120, 312 hrs postdose in Cycle 4; Predose in all later cycles. Maximum infusion length = 2 hrs.
10. Half-life (t1/2) of RO6895882 [ Time Frame: Baseline up to 28-days after last dose (up to approximately 25 months) (please see outcome measure description for detailed time frame) ]
    Part 1: Predose (Hr 0), 1 hr post SoI, at EoI, 2, 4, 24, 72, 96, 216 hrs post Day 1 dose. Part 2/3: qw schedule (1 Cycle = 1 week): Predose, 1 hr post SoI, at EoI, 2, 4 hrs after EoI, 24, 72, 96 hrs postdose in Cycle 1, 5 (include 120 hrs postdose); Predose, 24, 96 hrs postdose in Cycle 2, 3, 4; Predose in any later cycle. Part 2/3: q2w schedule (1 Cycle = 2 weeks): Predose, 1 hr post SoI, at EoI, 2, 4, 24, 72, 96, 120, 168, 312 hrs postdose in Cycle 1, 4 (exclude 312 hrs postdose); Predose, 24, 96, 168 hrs postdose in Cycle 2; Predose in all later cycles. Part 2/3: q3w schedule (1 Cycle = 3 weeks): Predose, 1 hr post SoI, at EoI, 2, 4, 24, 72, 96, 120, 168, 312, 480 hrs postdose in Cycle 1; Predose, 24, 96, 312 hrs postdose in Cycle 2; Predose, at EoI, 1, 2, 4 hrs post EoI, 24, 72, 96, 120, 168, 312 hrs postdose in Cycle 3; Predose, 24, 72, 120, 312 hrs postdose in Cycle 4; Predose in all later cycles. Maximum infusion length = 2 hrs.

Secondary Outcome Measures :

1. Count of Cluster of Differentiation (CD) 4+ Cells Analyzed by Flow Cytometry [ Time Frame: Baseline up to 28-days after last dose (up to approximately 25 months) (please see outcome measure description for detailed time frame) ]
   Part 1: Predose (Hr 0), at EoI, Day (D) 2. Part 2/3: qw schedule (1 cycle = 1 week): Cycle (C) 1: Predose, at EoI, D2, D5; C2: Predose, at EoI, D2; C3: Predose, at EoI; C4: Predose. Part 2/3: q2w schedule (1 cycle = 2 weeks): C1, C4: Predose, at EoI, D2, D5, C2: Predose, at EoI, D2; C3: Predose, at EoI. Part 2/3: q3w schedule (1 cycle = 3 weeks): C1: Predose, at EoI, Day 2, 5, 14; C3: Predose, at EoI, Day 2, 5; C2, C4: Predose, at EoI, Day 2. Maximum infusion length = 2 hrs.
2. Count of CD8+ Cells Analyzed by Flow Cytometry [ Time Frame: Baseline up to 28-days after last dose (up to approximately 25 months) (please see outcome measure description for detailed time frame) ]
   Part 1: Predose (Hr 0), at EoI, Day (D) 2. Part 2/3: qw schedule (1 cycle = 1 week): Cycle (C) 1: Predose, at EoI, D2, D5; C2: Predose, at EoI, D2; C3: Predose, at EoI; C4: Predose. Part 2/3: q2w schedule (1 cycle = 2 weeks): C1, C4: Predose, at EoI, D2, D5, C2: Predose, at EoI, D2; C3: Predose, at EoI. Part 2/3: q3w schedule (1 cycle = 3 weeks): C1: Predose, at EoI, Day 2, 5, 14; C3: Predose, at EoI, Day 2, 5; C2, C4: Predose, at EoI, Day 2. Maximum infusion length = 2 hrs.
3. Count of B Lymphocyte Cells Analyzed by Flow Cytometry [ Time Frame: Baseline up to 28-days after last dose (up to approximately 25 months) (please see outcome measure description for detailed time frame) ]
   Part 1: Predose (Hr 0), at EoI, Day (D) 2. Part 2/3: qw schedule (1 cycle = 1 week): Cycle (C) 1: Predose, at EoI, D2, D5; C2: Predose, at EoI, D2; C3: Predose, at EoI; C4: Predose. Part 2/3: q2w schedule (1 cycle = 2 weeks): C1, C4: Predose, at EoI, D2, D5, C2: Predose, at EoI, D2; C3: Predose, at EoI. Part 2/3: q3w schedule (1 cycle = 3 weeks): C1: Predose, at EoI, Day 2, 5, 14; C3: Predose, at EoI, Day 2, 5; C2, C4: Predose, at EoI, Day 2. Maximum infusion length = 2 hrs
4. Count of Natural Killer (NK) Cells Analyzed by Flow Cytometry [ Time Frame: Baseline up to 28-days after last dose (up to approximately 25 months) (please see outcome measure description for detailed time frame) ]
   Part 1: Predose (Hr 0), at EoI, Day (D) 2. Part 2/3: qw schedule (1 cycle = 1 week): Cycle (C) 1: Predose, at EoI, D2, D5; C2: Predose, at EoI, D2; C3: Predose, at EoI; C4: Predose. Part 2/3: q2w schedule (1 cycle = 2 weeks): C1, C4: Predose, at EoI, D2, D5, C2: Predose, at EoI, D2; C3: Predose, at EoI. Part 2/3: q3w schedule (1 cycle = 3 weeks): C1: Predose, at EoI, Day 2, 5, 14; C3: Predose, at EoI, Day 2, 5; C2, C4: Predose, at EoI, Day 2. Maximum infusion length = 2 hrs
5. Count of Monocytes Cells Analyzed by Flow Cytometry [ Time Frame: Baseline up to 28-days after last dose (up to approximately 25 months) (please see outcome measure description for detailed time frame) ]
   Part 1: Predose (Hr 0), at EoI, Day (D) 2. Part 2/3: qw schedule (1 cycle = 1 week): Cycle (C) 1: Predose, at EoI, D2, D5; C2: Predose, at EoI, D2; C3: Predose, at EoI; C4: Predose. Part 2/3: q2w schedule (1 cycle = 2 weeks): C1, C4: Predose, at EoI, D2, D5, C2: Predose, at EoI, D2; C3: Predose, at EoI. Part 2/3: q3w schedule (1 cycle = 3 weeks): C1: Predose, at EoI, Day 2, 5, 14; C3: Predose, at EoI, Day 2, 5; C2, C4: Predose, at EoI, Day 2. Maximum infusion length = 2 hrs.
6. Percentage of Participants With Objective Response Assessed According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v 1.1) [ Time Frame: From Screening until disease progression or death (up to approximately 25 months) ]
7. Percentage of Participants With Stable Disease Assessed According to RECIST v 1.1 [ Time Frame: From Screening until disease progression or death (up to approximately 25 months) ]
8. Percentage of Participants With Disease Control Assessed According to RECIST v 1.1 [ Time Frame: From Screening until disease progression or death (up to approximately 25 months) ]
9. Progression-Free Survival Assessed According to RECIST v 1.1 [ Time Frame: From Screening until disease progression or death (up to approximately 25 months) ]

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Participants with confirmed advanced and/or metastatic solid tumor, with at least one tumor lesion of non-critical location accessible to biopsy who have progressed on the standard of care therapy
• Locally confirmed CEA expression in tumor tissue (more than [>] 20 percent (%) of tumor cells staining with at least moderate intensity) or centrally confirmed CEA expression if no archival tumor tissue and fresh biopsy is collected
• Radiologically measurable and clinically evaluable disease
• Life expectancy of greater than or equal to (>/=) 12 weeks
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1
• All acute toxic effects of any prior radiotherapy, chemotherapy or surgical procedure must have resolved to Grade </=1, except alopecia (any grade) and Grade 2 peripheral neuropathy
• Adequate hematological, liver, and renal function
• Negative serum pregnancy test within 7 days prior to study treatment in premenopausal women and women </=2 years after menopause
• Participants with Gilbert's syndrome will be eligible for the study. A diagnosis of Gilbert's syndrome will be based on the exclusion of other diseases based on the following criteria: (i) unconjugated hyperbilirubinemia noted on several occasions; (ii) no evidence of hemolysis (normal hemoglobin, reticulocyte count, and Lactate dehydrogenase); (iii) normal liver function tests; (iv) absence of other diseases associated with unconjugated hyperbilirubinemia

Exclusion Criteria:

• History or clinical evidence of central nervous system (CNS) primary tumors or metastases including leptomeningeal metastases unless they have been previously treated, are asymptomatic and have had no requirement for steroids or enzyme inducing anticonvulsants in the last 14 days before screening
• Participants with an active second malignancy (other than non-melanoma skin cancer, or cervical carcinoma in situ). Participants who have a history of malignancy are not considered to have an active malignancy if they have completed therapy and are considered by their treating physician to be at less than (<) 30% risk for relapse
• Evidence of significant, uncontrolled concomitant diseases which could affect compliance with the protocol or interpretation of results, including diabetes mellitus, history of relevant pulmonary disorders and known autoimmune diseases
• Uncontrolled hypertension (systolic >150 millimeter of mercury [mmHg] and/or diastolic >100 mmHg), unstable angina, congestive heart failure (CHF) of any New York Heart Association (NYHA) classification, serious cardiac arrhythmia requiring treatment (exceptions: atrial fibrillation, paroxysmal supraventricular tachycardia), history of myocardial infarction within 6 months of enrollment
• Active or uncontrolled infections
• Known infection with human immunodeficiency virus (HIV), seropositive status
• Positive test results for chronic hepatitis B infection (defined as positive Hepatitis B surface antigen [HBsAg] serology and/or HBcAb status)
• Positive test results for hepatitis C (hepatitis C virus [HCV] antibody serology testing)
• Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that would contraindicate the use of an investigational drug
• Pregnant or breast-feeding women
• Known hypersensitivity to any of the components of RO6895882
• Concurrent therapy with any other investigational drug
• Regular immunosuppressive therapy (that is, for organ transplantation, chronic rheumatologic disease)
• Chronic use of steroids (including inhaled) will not be allowed. Concurrent high doses of systemic corticosteroids. High dose is considered as >20 mg of dexamethasone a day (or equivalent) for >7 consecutive days
• Radiotherapy within the last 4 weeks before start of study drug treatment with the exception of limited field palliative radiotherapy for bone pain relief

Contacts and Locations

Locations

United States, New York

Memorial Sloan Kettering Cancer Center

New York, New York, United States, 10065

Denmark

Rigshospitalet, Onkologisk Klinik

København Ø, Denmark, 2100

Finland

Helsinki University Central Hospital; Dept of Oncology

Helsinki, Finland, 00029

France

Institut Gustave Roussy; Departement Oncologie Medicale

Villejuif, France, 94805

Netherlands

Antoni van Leeuwenhoek Ziekenhuis

Amsterdam, Netherlands, 1066 CX

VU MEDISCH CENTRUM; Dept. of Medical Oncology

Amsterdam, Netherlands, 1081 HV

Spain

Clinica Universitaria de Navarra; Servicio de oncología

Pamplona, Navarra, Spain, 31008

Hospital Univ Vall d'Hebron; Servicio de Oncologia

Barcelona, Spain, 08035

Switzerland

CHUV; Departement d'Oncologie

Lausanne, Switzerland, 1011

United Kingdom

Oxford University Hospitals NHS Trust - Churchill Hospital

Oxford, United Kingdom, OX3 7LE

Sponsors and Collaborators

Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

More Information

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT02004106
• Other Study ID Numbers: BP28920; 2013-003041-41 ( EudraCT Number )
• First Posted: December 6, 2013
• Last Update Posted: March 6, 2018
• Last Verified: March 2018