A Study of TAK-164 in Participants With Advanced Gastrointestinal (GI) Cancer Expressing Guanylyl Cyclase C (GCC)

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the safety of TAK-164 and to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) and schedule.

Detailed Description
-----------------
The drug being tested in this study is a novel antibody-drug conjugate (ADC) called TAK-164. TAK-164 is being evaluated in participants with advanced GCC-positive GI cancer (Part A) or colorectal carcinoma (CRC) and gastric carcinoma (Part B and Part C) to determine safety, tolerability, and pharmacokinetics (PK) and MTD/RP2D of TAK-164, as well as the preliminary efficacy. The study will include approximately 100 evaluable participants. In Part A (Escalation), approximately 25 participants with GI carcinoma will be enrolled. Those include participants with various GI malignancies such as carcinomas of esophagus, stomach, colon, and pancreas. The starting dose for Arm 1 will be 0.004 mg/kg of TAK-164 administered intravenously on Day 1 Q3W and the maximal dose will not exceed 0.19 mg/kg Q3W. In Part B (Expansion), approximately 50 participants will be enrolled to receive TAK-164 infusion at determined RP2D in Part A. Participants will follow the Q3W schedule and will be followed until PD, unacceptable toxicity, or until they choose to withdraw consent. In Part C (Imaging substudy to be conducted in the Netherlands only), approximately 25 participants with GCC-expressing metastatic colorectal carcinoma (mCRC) will be enrolled to receive 89Zr-TAK-164 and unlabeled TAK-164 at determined RP2D in Part A. This multi-center trial will be conducted in the United States and the Netherlands. The overall time to participate in this study is up to 55 months. Participants will attend an end of study (EOS) visit 30 days after the last dose of TAK-164 or just prior to the start of subsequent antineoplastic therapy, whichever occurs first.

Official Title
-----------------
An Open-Label, Dose Escalation, Phase 1, First-in-Human Study of TAK-164, an Antibody-Drug Conjugate, in Patients With Advanced Gastrointestinal Cancers Expressing Guanylyl Cyclase C

Conditions
-----------------
Gastrointestinal Neoplasms; Esophageal, Stomach, Pancreas, Colon Neoplasms; Malignant Tumors of Digestive Organ; Advanced Gastrointestinal Malignancies

Intervention / Treatment
-----------------
* Drug: TAK-164
* Drug: 89Zr-TAK-164


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically or cytologically confirmed measurable advanced and/or metastatic solid GI tumor that expresses GCC protein (H-score greater than or equal to [>=] 10), for which standard treatment is no longer effective or does not offer curative or life-prolonging benefit. For the escalation part of the study (Part A), GI malignancies include, but are not limited to, metastatic colorectal carcinoma (mCRC), gastric carcinoma, esophageal carcinoma, small intestine cancer, and pancreatic cancer. The expansion part of the study (Part B) is limited to participants with CRC expressing a high-level of GCC (H-Score >=150) and gastric carcinoma (H-Score >=10). Part C includes participants with CRC and gastric carcinoma (H-score >=10 for both indications). o Part B of the study will be limited to participants with 2 or 3 prior lines of systemic standard of care therapy. Male or female participants 18 years or older. Adequate bone marrow function, defined as an absolute neutrophil count (ANC) of >=1.5*10^9 per liter (/L), platelet count >=100*10^9/L, and hemoglobin >=9 gram per deciliter (g/dL). Receiving transfusions or hematopoietic growth factors to meet enrollment criteria is not allowed within 14 days preceding the first dose of study drug. Adequate hepatic function with total bilirubin less than or equal to (<=) 1.5* upper limit of normal (ULN), serum ALT and AST must be less than (<) 2.5*ULN (AST and ALT may be elevated up to 3*ULN if the elevation can be reasonably ascribed to the presence of metastatic disease in liver), serum albumin > 3.0 g/dL. Adequate renal function as defined by creatinine CL >= 60 milliliter per minute (mL/min). Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1. Life expectancy of at least 12 weeks. Completion of prior chemotherapy, biologic therapy, immunotherapy, or radiation therapy at least 4 weeks prior to enrollment. Resolution of all toxic effects of prior treatments (except alopecia) to Grade <=1 NCI CTCAE, version 5. A portion of participants should have tumors amenable for serial biopsy and a willingness to provide consent for pharmacodynamic assessment. Additionally for Part C (imaging sub study), participant must fulfill the following criteria: At least 1 extrahepatic metastatic lesion >=2 centimeter (cm) in the longest diameter. Exclusion Criteria: Treatment with anticancer chemotherapy or biologic therapy or with an experimental anticancer agent within 28 days of the initial dose of study drug. Diagnosed or treated for another malignancy within 2 years before administration of the first dose of study drug, or previously diagnosed with another malignancy and have any evidence of residual disease. Participants with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection. Participant has a history of severe allergic or anaphylactic reactions to recombinant proteins or excipients used in TAK-164 formulation or 89Zr-TAK-164 formulation. Use of strong cytochrome P3A (CYP3A) inhibitors and CYP3A inducers or inhibitors or modulators of P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) within 1 week before the first dose of study drug. For participants enrolled in studies in which tumor biopsies are obtained: Known bleeding diathesis or history of abnormal bleeding, or any other known coagulation abnormalities that would contraindicate the tumor biopsy procedure. Ongoing therapy with any anticoagulant or antiplatelet agents (example, aspirin, clopidogrel, heparin, or warfarin). Participant has concurrent alcohol abuse or a history of drug-induced liver injury (DILI).

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: Other
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A Escalation Stage: TAK-164 Q3W<br>TAK-164 0.004 milligram per kilogram (mg/kg) starting dose, intravenous infusion, until PD, unacceptable toxicity or discontinuation by participant. Dose escalation will be performed to determine the MTD and/or RP2D. | Drug: TAK-164<br>* TAK-164 intravenous infusion.<br>|
| Experimental: Part B Expansion Stage: TAK-164 Q3W<br>TAK-164, intravenous infusion, until PD, unacceptable toxicity or discontinuation by participant. TAK-164 RP2D dose to be decided based on safety, PK, pharmacodynamics and antitumor response data observed in Part A escalation stage. | Drug: TAK-164<br>* TAK-164 intravenous infusion.<br>|
| Experimental: Part C Imaging Substudy: 89Zr-TAK-164 and TAK-164<br>89Zr-TAK-164, intravenous infusion, followed by unlabeled TAK-164, intravenous infusion in combination with 89Zr-TAK-164, intravenous infusion, and further followed by unlabeled TAK-164, intravenous infusion, until PD, unacceptable toxicity or discontinuation by participant. TAK-164 recommended imaging dose (RID) or RP2D dose to be decided based on safety, PK, PD and antitumor response data observed in Part A escalation stage. | Drug: TAK-164<br>* TAK-164 intravenous infusion.<br>Drug: 89Zr-TAK-164<br>* 89Zr-TAK-164 intravenous infusion<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose-limiting Toxicities (DLTs) | DLTs were evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5. DLT was defined as any of the following adverse events (AEs) that occurred and were considered by the investigator to be related to therapy with study drug: hematologic toxicities were, Grade 4 neutropenia (absolute neutrophil count [ANC] less than (<) 500 cells/cubic millimeter [mm^3]), thrombocytopenia (platelets <25,000/mm^3), febrile neutropenia (ANC <1000/mm^3) with fever (greater than [>] 38.3 degree Celsius or sustained temperature of greater than or equal to (>=) 38 degree Celsius, Grade 3 or greater thrombocytopenia with clinically meaningful bleeding at any time, Grade 3 or greater nausea and/or emesis that occurs despite the use of optimal anti-emetic prophylaxis and Grade 3 or greater diarrhea that occurs despite optimal supportive care measures and any other Grade 3 or greater nonhematologic toxicity except brief (<1 week) Grade 3 fatigue. | Baseline up to Month 22 | 
| Percentage of Participants With Adverse Events (AEs) |  | From first dose of study drug up to 30 days following the last dose of study drug (up to 22 months) | 
| Percentage of Participants With Grade 3 or Above AEs | AE Grades were evaluated as per NCI CTCAE, version 5. Graded from Grade 1: Mild asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated, Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL), Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL, Grade 4: Life-threatening consequences; urgent intervention indicated, Grade 5: Death related AE. Higher grade indicates more severe condition. | From first dose of study drug up to 30 days following the last dose of study drug (up to 22 months) | 
| Percentage of Participants With Drug-related AEs |  | From first dose of study drug up to 30 days following the last dose of study drug (up to 22 months) | 
| Percentage of Participants With Drug-related Grade 3 or Above AEs | AE Grades were evaluated as per NCI CTCAE, version 5. Graded from Grade 1: mild asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated, Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL, Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL, Grade 4: Life-threatening consequences; urgent intervention indicated, Grade 5: death related AE. Higher grade indicates more severe condition. | From first dose of study drug up to 30 days following the last dose of study drug (up to 22 months) | 
| Percentage of Participants With Serious Adverse Events (SAEs) |  | From first dose of study drug up to 30 days following the last dose of study drug (up to 22 months) | 
| Percentage of Participants With AEs Leading to Discontinuation |  | From first dose of study drug up to 30 days following the last dose of study drug (up to 22 months) | 
| Recommended Phase 2 Dose (RP2D) of TAK-164 | RP2D was the highest safe dose that could be applied to the expansion phase. | Baseline up to Month 22 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax: Maximum Observed Plasma Concentration for TAK-164 |  | Cycles 1 and 2 Day 1 pre-dose and at multiple time points (up to 336 hours) post-dose (Cycle length = 21 days) | 
| Tmax: Time to Reach the Maximum Observed Plasma Concentration (Cmax) for TAK-164 |  | Cycles 1 and 2 Day 1 pre-dose and at multiple time points (up to 336 hours) post-dose (Cycle length = 21 days) | 
| AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration for TAK-164 |  | Cycles 1 and 2 Day 1 pre-dose and at multiple time points (up to 336 hours) post-dose (Cycle length = 21 days) | 
| Ctrough: Observed Concentration Measured at the End of a Dosing Interval for TAK-164 |  | Cycles 1 and 2 Day 1 pre-dose and at multiple time points (up to 336 hours) post-dose (Cycle length = 21 days) | 
| Overall Response Rate (ORR) | ORR was assessed by the investigator based on modified Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. ORR was defined as the percentage of participants who had complete response (CR) or partial response (PR). CR was defined as the disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to <10 millimeters (mm). PR was defined as at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum longest diameter. | From start of study treatment until the start of subsequent anti cancer therapy ( up to Month 22) | 
| Disease Control Rate (DCR) | DCR was defined as the percentage of participants with CR, PR or stable disease (SD). DCR was assessed based on modified RECIST version 1.1 criteria. CR was defined as the disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to <10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD was neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum longest diameter since the treatment started. | Baseline up to Month 22 | 
| Duration of Response (DOR) | DOR was defined as the time from the date of first documentation of a response (CR or PR) to the date of first documented PD or death due to any cause, whichever occurred first based on modified RECIST version 1.1 criteria. CR was defined as the disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to <10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum longest diameters. PD was >=20% increase in sum of diameters of target lesions, reference-smallest sum recorded in study (sum at baseline if that was smallest). Sum of diameters must have absolute increase of >=5 mm. Appearance of >=1 new lesions also considered PD. | From the date of first documentation of a response (CR or PR) to the date of first documented PD or death due to any cause, whichever occurred first (up to 22 months) | 
| Progression-free Survival (PFS) | PFS was defined as the time from date of first study drug administration to the day of first documented PD or death due to any cause, whichever occurred first according to modified RECIST version 1.1 criteria. PD was >= 20% increase in sum of diameters of target lesions, reference-smallest sum recorded in study (sum at baseline if that was smallest). Sum of diameters must have absolute increase of >=5 mm. Appearance of >=1 new lesions also considered PD. PFS was censored at the last response assessment that is stable disease or better, prior to receipt of subsequent anticancer therapy, if applicable. Participants with no post-baseline assessments was censored at Day 1. | From date of first study drug administration to the day of first documented PD or death due to any cause, whichever occurred first (up to 22 months) | 
| Number of Participants With Positive Antidrug Antibody (ADA) Levels in Serum |  | Baseline up to Month 22 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Drug Therapy