Study To Evaluate Safety, Pharmacokinetics, Pharmacodynam... | NCT04826003

Label	Type	Description	Intervention Names
Part I: Dose-escalation of RO7122290	Experimental	The dose-escalation of RO7122290 will use a QW dosing schedule of RO7122290 in combination with a Q3W dosing interval for cibisatamab with obinutuzumab pre-treatment. The starting dose for RO7122290 will be 35 mg, which represents the human equivalent dose for the minimal pharmacologically active dose (1 mg/kg) in mice.	Drug: RO7122290 Drug: Cibisatamab Drug: Obinutuzumab
Part II: Dose-expansion of RO7122290	Experimental	Part II of this study will evaluate selected dose levels of RO7122290 from Part I (a QW RO712290 administration in combination with a Q3W cibisatamab administration with obinutuzumab pre-treatment) in a Q3W regimen in combination with a Q3W cibisatamab administration with obinutuzumab pre-treatment.	Drug: RO7122290 Drug: Cibisatamab Drug: Obinutuzumab

Name	Type	Description	Arm Group Labels	Other Names
RO7122290	Drug	RO7122290 will be administered using a QW (Part I) or Q3W (Part I or Part II) schedule in combination with 100 mg cibisatamab Q3W with obinutuzumab pre-treatment. The maximum dose of RO7122290 to be explored in combination with cibisatamab with obinutuzumab pre-treatment in this study is 500 mg for the QW dosing interval (Part I) or 1500 mg for the Q3W dosing interval (Part I or Part II).

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Part I: Occurrence of dose-limiting toxicities	The DLT observation period is defined as a period of 21 days after the first administration of RO7122290 combined with cibisatamab. Additional days (maximum 3 days per dosing) are allowed in case of treatment delays for non-safety reasons. Participants are evaluable for DLT assessment, if they have received one dose of cibisatamab and at least two doses of RO7122290 during the DLT period.	Baseline up to 21 days
Percentage of Participants with Adverse Events	Incidence, nature, and severity of adverse events (AEs) graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5 with the exception of cytokine release syndrome (CRS), which is graded according to the ASTCT grading scale for CRS (with individual signs and symptoms of CRS graded separately using the CTCAE v5.0 grading scale)	Baseline up to 28 months

Secondary Outcomes

Measure	Description	Time Frame
Serum concentration of RO7122290 over time	Part I: Cycle 1: Day 1 (Predose, 15 minutes, 4h, 8h postdose); Day 2 (24h postdose); Day 4 (72h postdose); D8 (Predose, 15 minutes, 4h postdose), D9 (24h postdose); D12 (96h postdose); D15 (Predose, 15 minutes, 4h postdose); D16 (24h postdose); Cycle 2 Day 1 (Predose, 15 minutes postdose); D2 (24h postdose), D8 (Predose, 15 minutes, 4h postdose); D9 (24h postdose); D15 (Predose, 15 minutes postdose); Subsequent Cycles D1 (Predose, 15 minutes postdose); D8 (Predose, 15 minutes postdose); D15 ((Predose, 15 minutes postdose); Discontinuation visit; 28 Day Safety Follow Up Visit, 90 (±7 days) post last dose after last dose of RO7122290. Part II: Cycle 1 Day 1 (Predose, 15minutes 4h, 8h, postdose); Day 2; D4; D8; D9; D12 ; D15; Cycle 2, Day 1 (Predose, 15 minutes postdose); Day 2; D8; D9; D12; Subsequent Cycles Day 1 (Predose, 15 minutes postdose) D8; D16; Discontinuation visit; 28 Day Follow Up; Safety FU Visit. Each cycle is 21 days

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Histologically confirmed adenocarcinoma originating from the colon or rectum.
Metastatic disease (Stage IV American Joint Committee on Cancer, Version 7) not amenable to local treatment.
Tumors that are MSS (microsatellite-stable) or MSI-low (microsatellite instable low), as determined by a certified laboratory
Participants with tumors that have high CEACAM5 expression as determined by qRT-PCR in an archival tumor sample or if not available, in a fresh tumor biopsy and documented through central testing of a representative tumor tissue specimen performed at baseline
Experienced disease progression during or within 3 months following the last administration of approved standard therapies.
Eastern Cooperative Oncology Group Performance Status of 0 or 1.
Life expectancy of ≥12 weeks
Adequate organ functions.
Serum creatinine within normal limits or a calculated glomerular filtration rate of ≥ 60 mL/min/1.73 m2 for participants with serum creatinine levels above or below the institutional normal value.
Serum albumin ≥30 g/L (3.0 g/dL).
Lactate dehydrogenase ≤ 2.5 x ULN.
Adequate contraception

Exclusion Criteria:

Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases.
History of leptomeningeal disease
Non-irradiated tumor lesions > 2 cm at critical sites (e.g., paraspinal, paratracheal, mediastinal, precarnial, sub-glottal) where tumor swelling induced by cibisatamab is expected to lead to significant complications. Irradiation must be completed at least 14 days prior to initiation of study treatment.
Dyspnea or peripheral capillary oxygen saturation < 92% at rest at baseline for patients with bilateral lung lesions or metastases in the remaining lung following lobectomy or pneumonectomy
Pleural effusion requiring drainage procedures.
Pleural effusion and/or pleural lesions involving both lungs
Active interstitial lung disease (ILD), pneumonitis, or a history of ILD/pneumonitis requiring treatment with steroids or history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
Severe dyspnea at rest due to complications of advanced malignancy or requiring supplementary oxygen therapy.
Patients with > 10 bilateral pulmonary lesions
Patients with pulmonary miliary metastatic pattern (innumerable small lesions) or pulmonary lymphangitic carcinomatosis.
Significant cardiovascular/cerebrovascular disease within 6 months prior to Day 1 of study drug administration
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 ≥ 2 weeks prior to initiation of study treatment.
History of progressive multifocal leukoencephalopathy
Uncontrolled tumor-related pain.
Uncontrolled ascites requiring recurrent drainage procedures (QW or more frequently). Participants with indwelling catheters are allowed.
Patients with pericardial effusion.
Uncontrolled or symptomatic hypercalcemia
Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis for a more comprehensive list of autoimmune diseases and immune deficiencies).
Active tuberculosis that has required treatment within 3 years prior to initiation of study treatment or latent tuberculosis that has not been appropriately treated.
Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study.
History of malignancy other than CRC within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate > 90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer.
Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results, including diabetes mellitus, history of relevant pulmonary disorders, or other disease with ongoing fibrosis (such as scleroderma, pulmonary fibrosis, emphysema, neurofibromatosis, palmar/plantar fibromatosis).
Known active infection, or reactivation of a latent infection, whether bacterial, viral (including, but not limited to, Epstein-Barr virus infection), fungal, mycobacterial, or other pathogens (excluding fungal infections of nail beds), or any major episode of infection requiring hospitalization or treatment with systemic antibiotics (IV and oral antibiotic treatment must have been completed at least 4 and 2 weeks, respectively, prior to initiation of study treatment).
Prior allogeneic stem cell or solid organ transplantation.
Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications.
Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during study treatment.
History of chronic liver disease or evidence of hepatic cirrhosis.
Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding that give reasonable suspicion of a disease or condition that would contraindicate the use of an investigational drug.
History of severe allergic or anaphylactic reactions to monoclonal antibody therapy and to chimeric or humanized antibodies or fusion proteins.
Major surgery or significant traumatic injury < 28 days prior to the first obinutuzumab infusion (excluding biopsies) or anticipation of the need for major surgery during study treatment.
Treatment with any systemic anti-cancer therapy, including chemotherapy or hormonal therapy, within 28 days prior to initiation of study treatment
Prior treatment with T-cell bispecifics (TCBs), CD137 (4-1BB) agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies, unless discussed and agreed by the Sponsor.
Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and IL-2) within 4 weeks or 5 half-lives (whatever if longer) prior to initiation of study treatment.
Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-alpha agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment.
Adverse events from prior anti-cancer therapy that have not resolved to Grade 1 or better with the exception of alopecia of any grade and Grade ≤ 2 peripheral neuropathy.
Known hypersensitivity to Chinese hamster ovary cell products.
Known allergy or hypersensitivity to any of the study drugs or any of their excipients.
Any participant actively taking anti platelet medication (aspirin, clopidogrel, ticagrelor, etc.) or any participant who is fully anti coagulated with warfarin, low molecular weight heparin or a novel oral anti-coagulant including dabigatran, rivaroxaban, epixaban, etc.
Pregnancy or breastfeeding, or intention of becoming pregnant during the study.

Facility	Status	City	State	ZIP	Country	Contacts
Rigshospitalet		København Ø		2100	Denmark
NKI/AvL

ID	Term
D007414	Intestinal Neoplasms
D005770	Gastrointestinal Neoplasms
D004067	Digestive System Neoplasms
D009371	Neoplasms by Site
D009369	Neoplasms
D004066	Digestive System Diseases
D005767	Gastrointestinal Diseases
D003108	Colonic Diseases
D007410	Intestinal Diseases
D012002	Rectal Diseases