Clinical trial NCT03539484: A Study of RO7172508 in Patients With Locally Advanced and/or Metastatic CEA-Positive Solid Tumors
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Solid Tumors
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2018-05-29
Enrollment: 26
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Number of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: Up to approximately 12 months
measure: Percentage of Participants With Adverse Events
timeFrame: 60 days after last dose of study treatment (up to approximately 12 months)
Secondary outcomes:
measure: Maximum Concentration of RO7172508
timeFrame: Cycle 1 following single dose administration of RO7172508
measure: Time of Maximum Concentration of RO7172508
timeFrame: Cycle 1 following single dose administration of RO7172508
measure: Clearance or Apparent Clearance of RO7172508
timeFrame: Cycle 1 following single dose administration of RO7172508
measure: Volume of Distribution at Steady State of RO7172508
timeFrame: Cycle 1 following single dose administration of RO7172508
measure: Area Under the Plasma Concentration Time-Curve From Zero to the Last Measured Concentration (AUClast) of RO7172508
timeFrame: Cycle 1 following single dose administration of RO7172508
measure: Area Under the Serum Concentration Versus Time Curve Computed From Time of Dosing to Infinity (AUCinf) of RO7172508
timeFrame: Cycle 1 following single dose administration of RO7172508
measure: Dose Normalized Area Under the Serum Concentration Versus Time Curve Computed From Time of Dosing to Infinity (AUCinf/Dose) of RO7172508
timeFrame: Cycle 1 following single dose administration of RO7172508
measure: Half-Life of RO7172508
timeFrame: Cycle 1 following single dose administration of RO7172508
measure: Presence or Absence and Titer of ADAs
timeFrame: Up to approximately 12 months
measure: Changes in Frequency of Tumor Infiltrating Lymphocytes
timeFrame: Cycle 1 Day 1 (Pre-treatment), Cycle 2 Day 8 (Cycle is 21 days)
measure: Secondary: Changes in Activation Status of Tumor Infiltrating Lymphocytes (% of CD8)
timeFrame: Cycle 1 Day 1 (Pre-treatment), Cycle 2 Day 8 (Cycle is 21 days)
measure: Changes in Activation Status of Tumor Infiltrating Lymphocytes (% of CD4)
timeFrame: Cycle 1 Day 1 (Pre-treatment), Cycle 2 Day 8 (Cycle is 21 days)
measure: Changes in Spatial Distribution of Tumor Infiltrating Lymphocytes
timeFrame: Cycle 1 Day 1 (Pre-treatment), Cycle 2 Day 8 (Cycle is 21 days)
measure: Objective Response Rate (ORR)
timeFrame: Up to approximately 12 months
measure: Disease Control Rate (DCR)
timeFrame: Up to approximately 12 months
measure: Duration of Response (DOR)
timeFrame: Up to approximately 12 month
measure: Progression Free Survival (PFS)
timeFrame: Up to approxmately 12 months
Other outcomes:
Locations:
city: Bruxelles
country: Belgium
facility: Cliniques Universitaires St-Luc
city: Toronto
country: Canada
facility: Princess Margaret Cancer Center
state: Ontario
city: København Ø
country: Denmark
facility: Rigshospitalet; Onkologisk Klinik
city: Pamplona
country: Spain
facility: Clinica Universitaria de Navarra
state: Navarra
city: Barcelona
country: Spain
facility: Hospital Univ Vall d'Hebron; Servicio de Oncologia
city: Madrid
country: Spain
facility: START Madrid. Centro Integral Oncologico Clara Campal; CIOCC
Study officials:
References: