A Study of RO6958688 in Participants With Locally Advanced and/or Metastatic Carcinoembryonic Antigen Positive Solid Tumors

Solid Tumors Clinical Trial

Official title:

An Open-Label, Multicenter, Dose-Escalation Phase I Study to Evaluate the Safety, Pharmacokinetics, and Therapeutic Activity of RO6958688, A Novel T-cell Bispecific Antibody That Targets the Human Carcinoembryonic Antigen (CEA) on Tumor Cells and CD3 on T Cells, Administered Intravenously in Patients With Locally Advanced and/or Metastatic CEA(+) Solid Tumors

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02324257
• Other study ID #: BP29541
• Secondary ID: 2014-003075-30RG
• Status: Completed
• Phase: Phase 1
• Start date: December 30, 2014
• Est. completion date: September 3, 2019

Study information

• Verified date: April 2020
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Study BP29541 is a first-in-human, open-label, multi-center, dose-escalation Phase I clinical study of single-agent RO6958688 in participants with locally advanced and/or metastatic carcinoembryonic antigen (CEA) positive solid tumors who have progressed on standard treatment, are intolerant to standard of care (SOC), and/or are non-amenable to SOC. The study will be conducted in two parts. Part I of the study will investigate the safety and pharmacokinetics of a single dose of RO6958688 in single participant cohorts with dosing starting from a minimal anticipated biological effect level dose of 0.05 milligrams (mg) and up to a maximum dose of 2.5 mg. Part II will establish the appropriate therapeutic dose based on safety, pharmacokinetics, and the maximum tolerated dose (MTD) of RO6958688 for the once per week (QW) regimen, every three weeks (Q3W) regimen, and for the step up dosing regimen.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 149
• Est. completion date: September 3, 2019
• Est. primary completion date: September 3, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• For dose escalation, locally advanced and/or metastatic gastrointestinal (GI) solid tumor in participants who have progressed on a standard therapy, are intolerant to SOC, and/or are non-amenable to SOC and other solid tumors expressing CEA. Only locally advanced and/or metastatic colorectal cancer participants should be included in the scheduled comparison expansion

• Radiologically measurable disease according to RECIST v1.1

• Life expectancy, in the opinion of the investigator of greater than or equal (>/=) to 12 weeks and LDH= 2.5 x ULN

• Eastern Cooperative Oncology Group Performance Status of 0-1

• All acute toxic effects of any prior radiotherapy, chemotherapy, or surgical procedure must have resolved to Grade less than or equal to 1 or returned to baseline except alopecia (any grade) and Grade 2 peripheral neuropathy

• Adequate hematological, liver, and renal function

• Participants must agree to remain abstinent or be willing to use effective methods of contraception as defined in the protocol

• Non-GI solid tumors (like non-small cell lung cancer or breast cancer) should have confirmed CEA expression in tumor tissue >/= 20% of tumor cells staining with at least moderate to high intensity of CEA expression are required (immunohistochemistry [IHC]2+ and IHC 3+). For CRC, pancreatic and gastric cancer participants, the CEA assessment will be performed retrospectively and the result is not needed to enroll the participant

Exclusion Criteria:

• Participants with a history or clinical evidence of central nervous system 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

• Spinal cord compression not definitively treated with surgery and/or radiation or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for at least 2 weeks prior to enrollment

• Leptomeningeal disease

• Participants with paraspinal, paratracheal and mediastinal pathologic lesions larger than 2 centimeters unless they are previously irradiated. Irradiation of lesions must be completed at least 14 days prior to initiation of study treatment

• Participants with another invasive malignancy in the last 2 years (with the exception of basal cell carcinoma and tumors deemed by the investigator to be of low likelihood for recurrence)

• Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results or contraindicate the use of an investigational drug, including diabetes mellitus, history of relevant cardio-pulmonary disorders, and known autoimmune diseases

• Participants with bilateral lung lesions and dyspnea and/or with bilateral lung lesions and an oxygen saturation (SaO2) level less than 92% or participants with lobectomy or pneumonectomy with lung metastases in the remaining lung and either dyspnea or SaO2 less than 92% at baseline

• Uncontrolled hypertension (systolic blood pressure [BP] greater than [>] 150 millimeters of mercury [mmHg] and/or diastolic BP > 100 mmHg), unstable angina, congestive heart failure of any New York Heart Association classification, serious cardiac arrhythmia that requires treatment with the exceptions of atrial fibrillation and paroxysmal supraventricular tachycardia, and history of myocardial infarction within 6 months of enrollment

• Active or uncontrolled infections

• Known human immunodeficiency virus (HIV) or known active hepatitis B or hepatitis C infection for participants not receiving obinutuzumab pretreatment

• Known HIV (HIV testing will be performed at screening if required by local regulations) in participants to be pretreated with obinutuzumab

• Pregnant or breastfeeding women

• Known hypersensitivity to any of the components of RO6958688 and/or obinutuzumab

• Concurrent therapy with any other investigational drug

• Last dose of any chemotherapy less than 28 days prior to the first RO6958688 infusion

• Expected need for regular immunosuppressive therapy

• Regular dose of corticosteroids the 28 days prior to Day 1 of this study or anticipated need for corticosteroids that exceeds prednisone 10 mg/day or equivalent within 28 days prior to the first RO6958688 infusion. Inhaled and topical steroids are permitted

• Radiotherapy within the last 28 days prior to the first RO6958688 infusion with the exception of limited-field palliative radiotherapy.

Additional Exclusion Criteria for Participants to be Pretreated with Obinutuzumab:

• Positive test results for human T-lymphotropic virus 1 (HTLV-1) or active HIV infection

• Positive test results for chronic hepatitis B infection or hepatitis C

• Known active tuberculosis (TB) requiring treatment within 3 years prior to baseline or latent TB that has not been appropriately treated

• Active bacterial, viral, fungal, or other infection, or any major episode of infection requiring treatment with intravenous (IV) antibiotics within 4 weeks of Cycle 1, Day 1

• Known hypersensitivity to any of the components of obinutuzumab; hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies

• History of progressive multifocal leukoencephalopathy (PML)

Related Conditions & MeSH terms

• Neoplasms
• Solid Tumors

Intervention

Drug:
• RO6958688
RO6958688 is given as an intravenous (IV) infusion as a single administration in Part I, and QW, Q3W, or as a combined QW/Q3W step up dosing regimen (cycle = 7 days in the QW regimen and cycle = 21 days in the Q3W regimen) in Part II of the study.
• Obinutuzumab
Obinutuzumab is given as an IV infusion at a dose level of 2000 mg on Day -13 or 1000 mg on Days -13 and -12 prior to the treatment start with RO6958688 on Cycle 1 Day 1.
• Tocilizumab
Tocilizumab will be administered as an IV infusion as necessary to treat adverse events.

Locations

Country	Name	City	State
Canada	Princess Margaret Cancer Center	Toronto	Ontario
Denmark	Rigshospitalet; Onkologisk Klinik	København Ø
France	Centre Leon Berard; Departement Oncologie Medicale	Lyon
Italy	IRCCS IST. Tumori Fondaz. Pascale; S.C. Oncologia Medica,Melanoma,Immunoterapia E Terapie Innovative	Napoli	Campania
Italy	Azienda Ospedaliera Universitaria Senese, U.O.C. Immunoterapia Oncologica	Siena	Toscana
Netherlands	Antoni van Leeuwenhoek Ziekenhuis	Amsterdam
Spain	Hospital del Mar; Servicio de Oncologia	Barcelona
Spain	Hospital Univ Vall d'Hebron; Servicio de Oncologia	Barcelona
Spain	Hospital Universitario 12 de Octubre; Servicio de Oncologia	Madrid
Spain	START Madrid-FJD, Hospital Fundacion Jimenez Diaz	Madrid
Spain	START Madrid. Centro Integral Oncologico Clara Campal; CIOCC	Madrid
Spain	Clinica Universitaria de Navarra; Servicio de Oncologia	Pamplona	Navarra
United States	University Of Colorado	Aurora	Colorado
United States	Dana Farber - Harvard	Boston	Massachusetts
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Sarah Cannon Cancer Center	Germantown	Tennessee
United States	Cedars Sinai Medical Center; Samuel-Oschin Comprehensive Cancer Institute	Los Angeles	California
United States	Yale Cancer Center; Medical Oncology	New Haven	Connecticut
United States	Columbia University Medical Center	New York	New York
United States	Stanford University	Palo Alto	California
United States	UCLA Cancer Center	Santa Monica	California

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Canada,  Denmark,  France,  Italy,  Netherlands,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants with Adverse Events (AEs) or Serious Adverse Events (SAEs)		Baseline up to 60 months
Primary	Percentage of Participants with Dose-Limiting Toxicities (DLTs)		Day 1 up to Day 21
Primary	Percentage of Participants With Anti-Drug Antibodies (ADAs) Against RO6958688	Part I: Pre-dose (Hour 0) on Day 1 of Cycles 1, 2-3; 120 hours after end of infusion (EOI) in Cycle 1. Part II QW: pre-dose (Hour 0) on Day 1 of Cycles 1, 2, 3, 4. Part II Q3W: pre-dose (Hour 0) on Day 1 of Cycles 1, 2, 3, 4; 120 hours and 336 hours after EOI in Cycle 1, and 120 hours after EOI in Cycles 2, 3, 4. For Part I and II (QW and Q3W): pre-dose (Hour 0) on Day 1 of every cycle after Cycle 4 (Cycle 3 for Part I) up to treatment discontinuation (approximately 60 months), 28 days after last dose (approximately 60 months) (Cycle = 7 days for Part I and II QW; 21 days for Part II Q3W) (infusion duration = 30 minutes for Part I and 120 minutes for Part II [QW and Q3W])	Pre-dose (Hour 0) on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome description section)
Primary	MTD of RO6958688 With/Without Obinutuzumab Pretreatment		Day 1 up to Day 21
Primary	Late Cycle MTD of RO6958688 Without Obinutuzumab Pretreatment for the Step up Dosing Regimen	Late cycle MTD is defined as the highest dose with less than or equal to DLT having been observed for 6 evaluable participants. If more than 6 participants are evaluable for DLT, late cycle MTD is the highest dose where less than (<) 33% of participants have DLT.	Day 1 up to Day 7 of each cycle as long as the dose is escalated weekly in Part II QW (up to approximately 60 months; Cycle = 7 days)
Primary	Maximum Serum Concentration (Cmax) for RO6958688	Part I: Pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2-3; 24, 48, and 120 hours after EOI of Cycle 1. Part II QW: pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2, 3, and 4; 24 and 120 hours after EOI of Cycles 1 and 2; 48 hours after EOI of Cycle 1. Part II Q3W: pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2, 3, and 4; 24, 48, 120, and 336 hours after EOI of Cycle 1; 24 and 120 hours after EOI of Cycles 2, 3, and 4; 48 hours after EOI of Cycle 2. For Part I and II (QW and Q3W): pre-dose (Hour 0), EOI, 2 hours after EOI (only for Part I) on Day 1 of every cycle after Cycle 4 (Cycle 3 for Part I), 2 hours after EOI on Day 1 of Cycles 8 and 12 (only for Part II QW) up to treatment discontinuation (approximately 60 months), 28 days after last dose (approximately 60 months) (Cycle =7 days for Part I and II QW; 21 days for Part II Q3W) (infusion duration = 30 minutes for Part I and 120 minutes for Part II [QW and Q3W])	Pre-dose (Hour 0) on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome description section)
Primary	Area Under the Concentration-Time Curve (AUC) for RO6958688	Part I: Pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2-3; 24, 48, and 120 hours after EOI of Cycle 1. Part II QW: pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2, 3, and 4; 24 and 120 hours after EOI of Cycles 1 and 2; 48 hours after EOI of Cycle 1. Part II Q3W: pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2, 3, and 4; 24, 48, 120, and 336 hours after EOI of Cycle 1; 24 and 120 hours after EOI of Cycles 2, 3, and 4; 48 hours after EOI of Cycle 2. For Part I and II (QW and Q3W): pre-dose (Hour 0), EOI, 2 hours after EOI (only for Part I) on Day 1 of every cycle after Cycle 4 (Cycle 3 for Part I), 2 hours after EOI on Day 1 of Cycles 8 and 12 (only for Part II QW) up to treatment discontinuation (approximately 60 months), 28 days after last dose (approximately 60 months) (Cycle =7 days for Part I and II QW; 21 days for Part II Q3W) (infusion duration = 30 minutes for Part I and 120 minutes for Part II [QW and Q3W])	Pre-dose (Hour 0) on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome description section)
Primary	Half-Life (t1/2) of RO6958688	Part I: Pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2-3; 24, 48, and 120 hours after EOI of Cycle 1. Part II QW: pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2, 3, and 4; 24 and 120 hours after EOI of Cycles 1 and 2; 48 hours after EOI of Cycle 1. Part II Q3W: pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2, 3, and 4; 24, 48, 120, and 336 hours after EOI of Cycle 1; 24 and 120 hours after EOI of Cycles 2, 3, and 4; 48 hours after EOI of Cycle 2. For Part I and II (QW and Q3W): pre-dose (Hour 0), EOI, 2 hours after EOI (only for Part I) on Day 1 of every cycle after Cycle 4 (Cycle 3 for Part I), 2 hours after EOI on Day 1 of Cycles 8 and 12 (only for Part II QW) up to treatment discontinuation (approximately 60 months), 28 days after last dose (approximately 60 months) (Cycle =7 days for Part I and II QW; 21 days for Part II Q3W) (infusion duration = 30 minutes for Part I and 120 minutes for Part II [QW and Q3W])	Pre-dose (Hour 0) on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome description section)
Primary	Clearance (CL) of RO6958688	Part I: Pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2-3; 24, 48, and 120 hours after EOI of Cycle 1. Part II QW: pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2, 3, and 4; 24 and 120 hours after EOI of Cycles 1 and 2; 48 hours after EOI of Cycle 1. Part II Q3W: pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2, 3, and 4; 24, 48, 120, and 336 hours after EOI of Cycle 1; 24 and 120 hours after EOI of Cycles 2, 3, and 4; 48 hours after EOI of Cycle 2. For Part I and II (QW and Q3W): pre-dose (Hour 0), EOI, 2 hours after EOI (only for Part I) on Day 1 of every cycle after Cycle 4 (Cycle 3 for Part I), 2 hours after EOI on Day 1 of Cycles 8 and 12 (only for Part II QW) up to treatment discontinuation (approximately 60 months), 28 days after last dose (approximately 60 months) (Cycle =7 days for Part I and II QW; 21 days for Part II Q3W) (infusion duration = 30 minutes for Part I and 120 minutes for Part II [QW and Q3W])	Pre-dose (Hour 0) on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome description section)
Primary	Volume of Distribution at Steady State (Vss) of RO6958688	Part I: Pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2-3; 24, 48, and 120 hours after EOI of Cycle 1. Part II QW: pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2, 3, and 4; 24 and 120 hours after EOI of Cycles 1 and 2; 48 hours after EOI of Cycle 1. Part II Q3W: pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2, 3, and 4; 24, 48, 120, and 336 hours after EOI of Cycle 1; 24 and 120 hours after EOI of Cycles 2, 3, and 4; 48 hours after EOI of Cycle 2. For Part I and II (QW and Q3W): pre-dose (Hour 0), EOI, 2 hours after EOI (only for Part I) on Day 1 of every cycle after Cycle 4 (Cycle 3 for Part I), 2 hours after EOI on Day 1 of Cycles 8 and 12 (only for Part II QW) up to treatment discontinuation (approximately 60 months), 28 days after last dose (approximately 60 months) (Cycle =7 days for Part I and II QW; 21 days for Part II Q3W) (infusion duration = 30 minutes for Part I and 120 minutes for Part II [QW and Q3W])	Pre-dose (Hour 0) on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome description section)
Primary	Minimum Drug Concentration (Cmin) for RO6958688	Part I: Pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2-3; 24, 48, and 120 hours after EOI of Cycle 1. Part II QW: pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2, 3, and 4; 24 and 120 hours after EOI of Cycles 1 and 2; 48 hours after EOI of Cycle 1. Part II Q3W: pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2, 3, and 4; 24, 48, 120, and 336 hours after EOI of Cycle 1; 24 and 120 hours after EOI of Cycles 2, 3, and 4; 48 hours after EOI of Cycle 2. For Part I and II (QW and Q3W): pre-dose (Hour 0), EOI, 2 hours after EOI (only for Part I) on Day 1 of every cycle after Cycle 4 (Cycle 3 for Part I), 2 hours after EOI on Day 1 of Cycles 8 and 12 (only for Part II QW) up to treatment discontinuation (approximately 60 months), 28 days after last dose (approximately 60 months) (Cycle =7 days for Part I and II QW; 21 days for Part II Q3W) (infusion duration = 30 minutes for Part I and 120 minutes for Part II [QW and Q3W])	Pre-dose (Hour 0) on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome description section)
Primary	Cmax for Obinutuzumab		Screening (pre-obinutuzumab dose [Hour 0] and EOI on Day -13 or Days -13 and -12), pre-RO6958688 dose [Hour 0] on Day 1 of Cycles 1, 2, 4, 8, and 12 in Part II QW (Cycle = 7 days)
Primary	Cmin for Obinutuzumab		Screening (pre-obinutuzumab dose [Hour 0] and EOI on Day -13 or Days -13 and -12), pre-RO6958688 dose [Hour 0] on Day 1 of Cycles 1, 2, 4, 8, and 12 in Part II QW (Cycle = 7 days)
Secondary	Percentage of Participants With an Objective Response of Complete Response (CR) or Partial Response (PR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version (v)1.1	Baseline up to 60 months (assessed at Screening, at 12 weeks [in Part I], at 8 weeks [in Part II QW and Q3W] after Cycle 1 Day 1, every 8 weeks for the first 12 months, thereafter every 12 weeks until disease progression or death whichever occurs first, up to 60 months) (Cycle = 7 days for Part I and II QW, and 21 days for Part II Q3W)	Baseline up to 60 months (detailed timeframe is provided in outcome description section)
Secondary	Duration of Response (DOR) According to RECIST v1.1	Baseline up to 60 months (assessed at Screening, at 12 weeks [in Part I], at 8 weeks [in Part II QW and Q3W] after Cycle 1 Day 1, every 8 weeks for the first 12 months, thereafter every 12 weeks until disease progression or death whichever occurs first, up to 60 months) (Cycle = 7 days for Part I and II QW, and 21 days for Part II Q3W)	Baseline up to 60 months (detailed timeframe is provided in outcome description section)
Secondary	Percentage of Participants With Stable Disease (SD) According to RECIST v1.1	Baseline up to 60 months (assessed at Screening, at 12 weeks [in Part I], at 8 weeks [in Part II QW and Q3W] after Cycle 1 Day 1, every 8 weeks for the first 12 months, thereafter every 12 weeks until disease progression or death whichever occurs first, up to 60 months) (Cycle = 7 days for Part I and II QW, and 21 days for Part II Q3W)	Baseline up to 60 months (detailed timeframe is provided in outcome description section)
Secondary	Percentage of Participants With Disease Control, Defined as PR+CR+SD, According to RECIST v1.1	Baseline up to 60 months (assessed at Screening, at 12 weeks [in Part I], at 8 weeks [in Part II QW and Q3W] after Cycle 1 Day 1, every 8 weeks for the first 12 months, thereafter every 12 weeks until disease progression or death whichever occurs first, up to 60 months) (Cycle = 7 days for Part I and II QW, and 21 days for Part II Q3W)	Baseline up to 60 months (detailed timeframe is provided in outcome description section)
Secondary	Progression-Free Survival (PFS) According to RECIST v1.1		From the first study treatment to the first occurrence of objective disease progression or death from any cause (up to 60 months)
Secondary	Change From Baseline in Activated Intra-Tumoral Cells		Baseline, Day 1 of Cycles 2, 3, 4, or 7 in Part II QW and Q3W (Cycle = 7 days for Part II QW and 21 days for Part II Q3W)
Secondary	Best Overall Response (BOR)	Baseline up to 60 months (assessed at Screening, at 12 weeks [in Part I], at 8 weeks [in Part II QW and Q3W] after Cycle 1 Day 1, every 8 weeks for the first 12 months, thereafter every 12 weeks until disease progression or death whichever occurs first, up to 60 months) (Cycle = 7 days for Part I and II QW, and 21 days for Part II Q3W)	Baseline up to 60 months (detailed timeframe is provided in outcome description section)