Clinical trial NCT02324257: A Study of RO6958688 in Participants With Locally Advanced and/or Metastatic Carcinoembryonic Antigen Positive Solid Tumors
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Solid Tumors
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2014-12-24
Enrollment: 149
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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)

Primary outcomes:
measure: Percentage of Participants with Adverse Events (AEs) or Serious Adverse Events (SAEs)
timeFrame: Baseline up to 60 months
measure: Percentage of Participants with Dose-Limiting Toxicities (DLTs)
timeFrame: Day 1 up to Day 21
measure: Percentage of Participants With Anti-Drug Antibodies (ADAs) Against RO6958688
timeFrame: Pre-dose (Hour 0) on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome description section)
measure: MTD of RO6958688 With/Without Obinutuzumab Pretreatment
timeFrame: Day 1 up to Day 21
measure: Late Cycle MTD of RO6958688 Without Obinutuzumab Pretreatment for the Step up Dosing Regimen
timeFrame: 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)
measure: Maximum Serum Concentration (Cmax) for RO6958688
timeFrame: Pre-dose (Hour 0) on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome description section)
measure: Area Under the Concentration-Time Curve (AUC) for RO6958688
timeFrame: Pre-dose (Hour 0) on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome description section)
measure: Half-Life (t1/2) of RO6958688
timeFrame: Pre-dose (Hour 0) on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome description section)
measure: Clearance (CL) of RO6958688
timeFrame: Pre-dose (Hour 0) on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome description section)
measure: Volume of Distribution at Steady State (Vss) of RO6958688
timeFrame: Pre-dose (Hour 0) on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome description section)
measure: Minimum Drug Concentration (Cmin) for RO6958688
timeFrame: Pre-dose (Hour 0) on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome description section)
measure: Cmax for Obinutuzumab
timeFrame: 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)
measure: Cmin for Obinutuzumab
timeFrame: 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 outcomes:
measure: 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
timeFrame: Baseline up to 60 months (detailed timeframe is provided in outcome description section)
measure: Duration of Response (DOR) According to RECIST v1.1
timeFrame: Baseline up to 60 months (detailed timeframe is provided in outcome description section)
measure: Percentage of Participants With Stable Disease (SD) According to RECIST v1.1
timeFrame: Baseline up to 60 months (detailed timeframe is provided in outcome description section)
measure: Percentage of Participants With Disease Control, Defined as PR+CR+SD, According to RECIST v1.1
timeFrame: Baseline up to 60 months (detailed timeframe is provided in outcome description section)
measure: Progression-Free Survival (PFS) According to RECIST v1.1
timeFrame: From the first study treatment to the first occurrence of objective disease progression or death from any cause (up to 60 months)
measure: Change From Baseline in Activated Intra-Tumoral Cells
timeFrame: 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)
measure: Best Overall Response (BOR)
timeFrame: Baseline up to 60 months (detailed timeframe is provided in outcome description section)
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Cedars Sinai Medical Center; Samuel-Oschin Comprehensive Cancer Institute
state: California
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: Santa Monica
country: United States
facility: UCLA Cancer Center
state: California
city: Aurora
country: United States
facility: University Of Colorado
state: Colorado
city: New Haven
country: United States
facility: Yale Cancer Center; Medical Oncology
state: Connecticut
city: Boston
country: United States
facility: Dana Farber - Harvard
state: Massachusetts
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Germantown
country: United States
facility: Sarah Cannon Cancer Center
state: Tennessee
city: Toronto
country: Canada
facility: Princess Margaret Cancer Center
state: Ontario
city: København Ø
country: Denmark
facility: Rigshospitalet; Onkologisk Klinik
city: Lyon
country: France
facility: Centre Leon Berard; Departement Oncologie Medicale
city: Napoli
country: Italy
facility: IRCCS IST. Tumori Fondaz. Pascale; S.C. Oncologia Medica,Melanoma,Immunoterapia E Terapie Innovative
state: Campania
city: Siena
country: Italy
facility: Azienda Ospedaliera Universitaria Senese, U.O.C. Immunoterapia Oncologica
state: Toscana
city: Amsterdam
country: Netherlands
facility: Antoni van Leeuwenhoek Ziekenhuis
city: Pamplona
country: Spain
facility: Clinica Universitaria de Navarra; Servicio de Oncologia
state: Navarra
city: Barcelona
country: Spain
facility: Hospital del Mar; Servicio de Oncologia
city: Barcelona
country: Spain
facility: Hospital Univ Vall d'Hebron; Servicio de Oncologia
city: Madrid
country: Spain
facility: START Madrid-FJD, Hospital Fundacion Jimenez Diaz
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre; Servicio de Oncologia
city: Madrid
country: Spain
facility: START Madrid. Centro Integral Oncologico Clara Campal; CIOCC
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Martinez-Sabadell A, Morancho B, Rius Ruiz I, Roman Alonso M, Ovejero Romero P, Escorihuela M, Chicote I, Palmer HG, Nonell L, Alemany-Chavarria M, Klein C, Bacac M, Arribas J, Arenas EJ. The target antigen determines the mechanism of acquired resistance to T cell-based therapies. Cell Rep. 2022 Oct 18;41(3):111430. doi: 10.1016/j.celrep.2022.111430.