Clinical trial NCT03449030: A Study of TAK-164 in Participants With Advanced Gastrointestinal (GI) Cancer Expressing Guanylyl Cyclase C (GCC)
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Gastrointestinal Neoplasms; Esophageal, Stomach, Pancreas, Colon Neoplasms; Malignant Tumors of Digestive Organ; Advanced Gastrointestinal Malignancies
Keywords: Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2018-02-28
Enrollment: 31
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: OTHER

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.

Eligibility criteria: Inclusion Criteria:

1. 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.
2. Male or female participants 18 years or older.
3. 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.
4. 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.
5. Adequate renal function as defined by creatinine CL \>= 60 milliliter per minute (mL/min).
6. Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1.
7. Life expectancy of at least 12 weeks.
8. Completion of prior chemotherapy, biologic therapy, immunotherapy, or radiation therapy at least 4 weeks prior to enrollment.
9. Resolution of all toxic effects of prior treatments (except alopecia) to Grade \<=1 NCI CTCAE, version 5.
10. 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:
11. At least 1 extrahepatic metastatic lesion \>=2 centimeter (cm) in the longest diameter.

Exclusion Criteria:

1. Treatment with anticancer chemotherapy or biologic therapy or with an experimental anticancer agent within 28 days of the initial dose of study drug.
2. 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.
3. 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.
4. 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.
5. 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).
6. Participant has concurrent alcohol abuse or a history of drug-induced liver injury (DILI).

Primary outcomes:
measure: Number of Participants With Dose-limiting Toxicities (DLTs)
timeFrame: Baseline up to Month 22
measure: Percentage of Participants With Adverse Events (AEs)
timeFrame: From first dose of study drug up to 30 days following the last dose of study drug (up to 22 months)
measure: Percentage of Participants With Grade 3 or Above AEs
timeFrame: From first dose of study drug up to 30 days following the last dose of study drug (up to 22 months)
measure: Percentage of Participants With Drug-related AEs
timeFrame: From first dose of study drug up to 30 days following the last dose of study drug (up to 22 months)
measure: Percentage of Participants With Drug-related Grade 3 or Above AEs
timeFrame: From first dose of study drug up to 30 days following the last dose of study drug (up to 22 months)
measure: Percentage of Participants With Serious Adverse Events (SAEs)
timeFrame: From first dose of study drug up to 30 days following the last dose of study drug (up to 22 months)
measure: Percentage of Participants With AEs Leading to Discontinuation
timeFrame: From first dose of study drug up to 30 days following the last dose of study drug (up to 22 months)
measure: Recommended Phase 2 Dose (RP2D) of TAK-164
timeFrame: Baseline up to Month 22
Secondary outcomes:
measure: Cmax: Maximum Observed Plasma Concentration for TAK-164
timeFrame: Cycles 1 and 2 Day 1 pre-dose and at multiple time points (up to 336 hours) post-dose (Cycle length = 21 days)
measure: Tmax: Time to Reach the Maximum Observed Plasma Concentration (Cmax) for TAK-164
timeFrame: Cycles 1 and 2 Day 1 pre-dose and at multiple time points (up to 336 hours) post-dose (Cycle length = 21 days)
measure: AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration for TAK-164
timeFrame: Cycles 1 and 2 Day 1 pre-dose and at multiple time points (up to 336 hours) post-dose (Cycle length = 21 days)
measure: Ctrough: Observed Concentration Measured at the End of a Dosing Interval for TAK-164
timeFrame: Cycles 1 and 2 Day 1 pre-dose and at multiple time points (up to 336 hours) post-dose (Cycle length = 21 days)
measure: Overall Response Rate (ORR)
timeFrame: From start of study treatment until the start of subsequent anti cancer therapy ( up to Month 22)
measure: Disease Control Rate (DCR)
timeFrame: Baseline up to Month 22
measure: Duration of Response (DOR)
timeFrame: 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)
measure: Progression-free Survival (PFS)
timeFrame: 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)
measure: Number of Participants With Positive Antidrug Antibody (ADA) Levels in Serum
timeFrame: Baseline up to Month 22
Other outcomes:
Locations:
city: Aurora
country: United States
facility: University of Colorado Cancer Center
state: Colorado
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Nashville
country: United States
facility: SCRI - Tennessee Oncology Nashville - Southern Hills Clinic
state: Tennessee
Study officials:
affiliation: Millennium Pharmaceuticals, Inc.
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Abu-Yousif AO, Cvet D, Gallery M, Bannerman BM, Ganno ML, Smith MD, Lai KC, Keating TA, Stringer B, Kamali A, Eng K, Koseoglu S, Zhu A, Xia CQ, Landen MS, Borland M, Robertson R, Bolleddula J, Qian MG, Fretland J, Veiby OP. Preclinical Antitumor Activity and Biodistribution of a Novel Anti-GCC Antibody-Drug Conjugate in Patient-derived Xenografts. Mol Cancer Ther. 2020 Oct;19(10):2079-2088. doi: 10.1158/1535-7163.MCT-19-1102. Epub 2020 Aug 11.