A Study of RO7172508 in Patients With Locally Advanced and/or Metastatic CEA-Positive Solid Tumors

Solid Tumors Clinical Trial

Official title:

A First-in-Human, Open-Label, Multicenter, Dose-Escalation Phase I Clinical Study of Single-Agent RO7172508 in Patients With Locally Advanced and/or Metastatic CEA-Positive Solid Tumors

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03539484
• Other study ID #: BP40092
• Status: Terminated
• Phase: Phase 1
• Start date: July 4, 2018
• Est. completion date: July 22, 2019

Study information

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

Clinical Trial Summary

This study was to determine the maximum-tolerated dose (MTD) and/or the optimal biological dose (OBD) as well as the optimal schedule for intravenous (IV) and subcutaneous (SC) administrations of RO7172508 as monotherapy, with or without obinutuzumab pre-treatment, in participants with locally advanced and/or metastatic carcinoembryonic antigen (CEA)-positive solid tumors who have progressed on standard of care (SOC) treatment, are intolerant to SOC, and/or are non-amenable to SOC. This study was conducted in two parts. Part I of the study consisted of an IV single participant cohort/multiple-ascending dose-escalation to evaluate the safety of RO7172508. Part II was a multiple participant cohort/multiple-ascending dose-escalation to define the MTD and/or OBD of RO7172508 administered as single agent, IV and/or SC, in participants with tumors that are expressing high as well as moderate/low-CEA. The study switched from Part I to Part II when the maximum planned dose for Part I was reached or the occurrence of a RO7172508-related Grade >= 2 adverse event (AE) or dose-limiting toxicity (DLT) was observed, whichever comes first. The Sponsor may decide to switch from Part I to Part II in the absence of an observed RO7172508-related Grade >= 2 toxicity or prior to maximum planned dose for Part I.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 26
• Est. completion date: July 22, 2019
• Est. primary completion date: July 22, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• For Part I: participants with locally advanced and/or metastatic solid tumor with confirmed cytoplasmic and/or membranous high CEA expression in tumor tissue is required. Participants must have progressed on a SOC therapy, be intolerant to SOC, and/or are non-amenable to SOC.

• For <12 mg dose cohorts, serum CEA levels below a certain threshold is required as follows:

• For dose cohorts 65-159 microgram, a sCEA level of < 22 ng/mL

• For dose cohorts 160-399 microgram, a sCEA level of < 28 ng/mL

• For dose cohorts 400-799 microgram, a sCEA level of < 44 ng/mL

• For dose cohorts 800-1599 microgram, a sCEA level of < 70 ng/mL

• For the dose cohort of 1.6-3.1 milligram, a sCEA level of < 123 ng/mL

• For the dose cohort of 3.2-6.3 milligram, an sCEA level of < 229 ng/mL.

• For the dose cohort of 6.4-11.9 milligram, an sCEA level of < 440 ng/mL. If dose fractionation is implemented, the sCEA threshold for inclusion should correspond to the dose range of the first dose administered.

• For Part II, participants with locally advanced and/or metastatic solid tumor expressing cytoplasmic and/or membranous high-CEA or moderate/low-CEA on archival material, who have progressed on a SOC therapy, are intolerant to SOC, and/or are non-amenable to SOC. Participants must have a lesion amenable to biopsy (except participants with NSCLC, which may be enrolled with archival tissue available only). For participants with colorectal cancer (CRC) only, the CEA assessment by immunohistochemistry should be performed but the result is not required to enroll the participant.

• Radiologically measurable disease according to RECIST v1.1.

• Life expectancy of >= 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 or returned to baseline except alopecia (any grade) and Grade 2 peripheral neuropathy.

• Adequate hematological, liver, renal, and lung function

• For women: agree to remain abstinent or use two contraceptive methods that result in a failure rate of <1% per year from screening until 2 months after the last dose of RO7172508 and have a negative pregnancy test within one week prior to the first study treatment administration

• For men: remain abstinent or use contraceptive measures such as a condom plus an additional contraceptive method that together result in a failure rate of <1% per year, with partners who are woman of childbearing potential and refrain from donating sperm during the study

Exclusion Criteria:

• History or clinical evidence of central nervous system (CNS) primary tumors or 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.

• Non-irradiated lesions > 2 cm at critical sites where tumor swelling induced by RO7172508 is expected to lead to significant complications.

• Another invasive malignancy in the last 2 years

• 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.

• Uncontrolled hypertension, unstable angina, congestive heart failure, 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 hepatitis B or C

• Major surgery or significant traumatic injury < 28 days prior to the first RO7172508 administration or anticipation of the need for major surgery during study treatment.

Specific Exclusion Criteria if Pre-treatment with Obinutuzumab is Implemented:

• Known HIV

• Positive test results for HBV infection, HBcAb indicating an active viral infection and positive test results for HCV.

• Participants positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA).

• History of progressive multifocal leukoencephalopathy.

• Active TB requiring treatment within 3 years prior to baseline.

• Latent TB diagnosed during Screening.

• Positive test results for human T-lymphotropic virus 1

Related Conditions & MeSH terms

• Neoplasms
• Solid Tumors

Intervention

Drug:
• RO7172508
RO7172508 was administered at a dose and as per the schedule specified in the respective arms.
• Obinutuzumab
In the event obinutuzumab treatment is implemented, obinutuzumab will be administered either on Day-7 or on Day-7 and Day-6. If obinutuzumab is given only on one day, then the schedule for Day-7 should be followed including an end of infusion sample.
• Tocilizumab
Tocilizumab was administered if required, for the management of severe CRS (cytokine release syndrome)

Locations

Country	Name	City	State
Belgium	Cliniques Universitaires St-Luc	Bruxelles
Canada	Princess Margaret Cancer Center	Toronto	Ontario
Denmark	Rigshospitalet; Onkologisk Klinik	København Ø
Spain	Hospital Univ Vall d'Hebron; Servicio de Oncologia	Barcelona
Spain	START Madrid. Centro Integral Oncologico Clara Campal; CIOCC	Madrid
Spain	Clinica Universitaria de Navarra	Pamplona	Navarra

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

Belgium,  Canada,  Denmark,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Dose Limiting Toxicities (DLTs)	Number of participants with DLTs.	Up to approximately 12 months
Primary	Percentage of Participants With Adverse Events	Percentage of participants with adverse events.	60 days after last dose of study treatment (up to approximately 12 months)
Secondary	Maximum Concentration of RO7172508		Cycle 1 following single dose administration of RO7172508
Secondary	Time of Maximum Concentration of RO7172508		Cycle 1 following single dose administration of RO7172508
Secondary	Clearance or Apparent Clearance of RO7172508		Cycle 1 following single dose administration of RO7172508
Secondary	Volume of Distribution at Steady State of RO7172508		Cycle 1 following single dose administration of RO7172508
Secondary	Area Under the Plasma Concentration Time-Curve From Zero to the Last Measured Concentration (AUClast) of RO7172508		Cycle 1 following single dose administration of RO7172508
Secondary	Area Under the Serum Concentration Versus Time Curve Computed From Time of Dosing to Infinity (AUCinf) of RO7172508		Cycle 1 following single dose administration of RO7172508
Secondary	Dose Normalized Area Under the Serum Concentration Versus Time Curve Computed From Time of Dosing to Infinity (AUCinf/Dose) of RO7172508		Cycle 1 following single dose administration of RO7172508
Secondary	Half-Life of RO7172508		Cycle 1 following single dose administration of RO7172508
Secondary	Presence or Absence and Titer of ADAs		Up to approximately 12 months
Secondary	Changes in Frequency of Tumor Infiltrating Lymphocytes		Cycle 1 Day 1 (Pre-treatment), Cycle 2 Day 8 (Cycle is 21 days)
Secondary	Secondary: Changes in Activation Status of Tumor Infiltrating Lymphocytes (% of CD8)		Cycle 1 Day 1 (Pre-treatment), Cycle 2 Day 8 (Cycle is 21 days)
Secondary	Changes in Activation Status of Tumor Infiltrating Lymphocytes (% of CD4)		Cycle 1 Day 1 (Pre-treatment), Cycle 2 Day 8 (Cycle is 21 days)
Secondary	Changes in Spatial Distribution of Tumor Infiltrating Lymphocytes	Spatial distribution of TIL's analyzed by performing IHC assay, which measures the density and intra-tumoral location of CD8+ T cells and reports "CD8 T cell immune phenotypes". These are classified as "desert", "excluded" and "inflamed".	Cycle 1 Day 1 (Pre-treatment), Cycle 2 Day 8 (Cycle is 21 days)
Secondary	Objective Response Rate (ORR)	Objective response was defined as a Complete Response (CR) or Parital Response (PR), as determined by the Investigator's assessment using RECIST v1.1 and confirmed by repeat assessments >= 4 weeks after initial documentation. To classify a response as SD, measurements are classified as stable (according to RECIST v1.1) at least once after study entry at a minimum of 6 weeks after study entry.	Up to approximately 12 months
Secondary	Disease Control Rate (DCR)	DCR is determined as the rate of participants with an observed tumor response of CR or PR (ORR) or CR, PR or SD (DCR). DCR is to be derived for RECIST v1.1.	Up to approximately 12 months
Secondary	Duration of Response (DOR)	Among participants with an objective response (responders), DOR will be defined as the time from first occurrence of a documented objective response until the time of documented disease progression or death within 30 days from last study treatment from any cause during treatment, whichever occurs first. This will be calculated for participants who have a best overall response of CR or PR as defined per RECIST v1.1 and per iRECIST.	Up to approximately 12 month
Secondary	Progression Free Survival (PFS)	PFS (on-treatment) will be defined as the time from study treatment initiation (Cycle 1 Day 1) to the first occurrence of documented disease progression or death from any cause during treatment (death within 30 days from last study treatment), whichever occurs first.	Up to approxmately 12 months