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

Study Overview
=================
Brief 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.

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

Conditions
-----------------
Solid Tumors

Intervention / Treatment
-----------------
* Drug: RO7172508
* Drug: Obinutuzumab
* Drug: Tocilizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part I: Single Participant Cohorts IV/MAD-Escalation<br>Part I was a multiple-ascending dose-escalation in single participant cohorts. RO7172508 was administered intravenously once every 3 weeks (Q3W). The starting dose of RO7172508 was 65 microgram (mcg) and the maximum dose explored was 1.6 milligram (mg). | Drug: RO7172508<br>* RO7172508 was administered at a dose and as per the schedule specified in the respective arms.<br>Drug: Tocilizumab<br>* Tocilizumab was administered if required, for the management of severe CRS (cytokine release syndrome)<br>|
| Experimental: Part II: Multiple Participant Cohorts IV/MAD-Escalation<br>Multiple ascending dose-escalation of IV-administered RO7172508 in multiple participant cohorts: The starting-dose for the initiation of the IV dose-escalation was determined by Part I and RO7172508 was initially given Q3W. Dose-escalation was undertaken based on safety until determination of the MTD or the highest safe dose if MTD is not reached. If on-target toxicity was reported in the first cycle of treatment, fractionated dosing may be implemented for the first cycle to improve tolerability. | Drug: RO7172508<br>* RO7172508 was administered at a dose and as per the schedule specified in the respective arms.<br>Drug: Obinutuzumab<br>* 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.<br>Drug: Tocilizumab<br>* Tocilizumab was administered if required, for the management of severe CRS (cytokine release syndrome)<br>|
| Experimental: Part II: Multiple Participant Cohorts SC/MAD-Escalation (QW)<br>Multiple ascending dose-escalation of SC-administered RO7172508 in multiple participant cohorts. These will be initiated once the IV schedule has shown RO7172508 preliminary clinical activity or the MTD has been established and is equal to or above 2 mg. The starting-dose and regimen once a week or once every 3 weeks (QW or Q3W) for SC administration will be proposed based on the evaluation of the safety and PK data observed following IV administration but will not exceed the highest safe dose tested in the IV Q3W dose escalation; a minimum dose of 2 mg is defined for a single SC administration. In addition, the QW SC starting-dose will not exceed one third of the IV MTD or of the highest safe IV dose tested. Dose escalation will continue based on safety until determination of the MTD or the planned maximum dose of 400 mg. If on-target toxicity is reported in the first cycle of treatment, fractionated dosing may be implemented for the first cycle to improve tolerability. | Drug: RO7172508<br>* RO7172508 was administered at a dose and as per the schedule specified in the respective arms.<br>Drug: Obinutuzumab<br>* 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.<br>Drug: Tocilizumab<br>* Tocilizumab was administered if required, for the management of severe CRS (cytokine release syndrome)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose Limiting Toxicities (DLTs) | Number of participants with DLTs. | Up to approximately 12 months | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Concentration of RO7172508 |  | Cycle 1 following single dose administration of RO7172508 | 
| Time of Maximum Concentration of RO7172508 |  | Cycle 1 following single dose administration of RO7172508 | 
| Clearance or Apparent Clearance of RO7172508 |  | Cycle 1 following single dose administration of RO7172508 | 
| Volume of Distribution at Steady State of RO7172508 |  | Cycle 1 following single dose administration of RO7172508 | 
| 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 | 
| 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 | 
| 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 | 
| Half-Life of RO7172508 |  | Cycle 1 following single dose administration of RO7172508 | 
| Presence or Absence and Titer of ADAs |  | Up to approximately 12 months | 
| Changes in Frequency of Tumor Infiltrating Lymphocytes |  | Cycle 1 Day 1 (Pre-treatment), Cycle 2 Day 8 (Cycle is 21 days) | 
| 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) | 
| Changes in Activation Status of Tumor Infiltrating Lymphocytes (% of CD4) |  | Cycle 1 Day 1 (Pre-treatment), Cycle 2 Day 8 (Cycle is 21 days) | 
| 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) | 
| 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 | 
| 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 | 
| 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 | 
| 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 |