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

Completed

Conditions: gastrointestinal cancers
10017990

Registration Number: NL-OMON48866

Lead Sponsor: Millenium Pharmaceuticals

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Completed

Sex: Not specified

Target Recruitment: 25

Inclusion Criteria

* Histologically or cytologically confirmed measurable advanced and/or
metastatic solid GI tumor that expresses GCC protein (H-score *10), for which
standard treatment is no longer effective or for whom there is no available
standard therapy. For the escalation part of the study (part A), GI
malignancies include, but are not limited to, mCRC, gastric carcinoma,
esophageal carcinoma, small intestine cancer, and pancreatic cancer. The
expansion part of the study (part B) is limited to patients with CRC expressing
a high-level GCC (H-score *150) and gastric carcinoma expressing GCC (H-score
*10). Part C includes patients with CRC and gastric carcinoma expressing GCC
(H-score *10).
* The expansion part of the study (part B) will be limited to patients with 2
or 3 prior lines of systemic
standard of care therapy.
* Voluntary written consent must be obtained from the patient prior to
enrollment in the study with the understanding that consent may be withdrawn by
the patient at any time without consequences on receiving future medical care.
* Male or female patients 18 years or older.
* Adequate bone marrow function, defined as an absolute neutrophil count of
*1.5 × 109/L, platelet count *100 × 109/L, and hemoglobin *9 g/dL. Receiving
transfusions or hematopoietic growth factors to meet enrollment criteria are
not allowed within 14 days preceding the first dose of study drug.
* Adequate hepatic function with:
* Total bilirubin *1.5 * upper limit of normal (ULN).
* Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
must be *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 clearance *60 mL/min.
* Eastern Cooperative Oncology Group 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 by National Cancer Institute
Common Terminology Criteria for Adverse Events, version 5.
* A portion of patients should have tumors amendable for serial biopsy and a
willingness to provide consent for pharmacodynamic assessment.

Additionally, for part C (imaging substudy), patients must fulfill the
following criteria:
* At least 1 extrahepatic metastatic lesion *2 cm in the longest diameter.

Exclusion Criteria

* Female patients who are lactating and breastfeeding or have a positive serum
pregnancy test during the screening period, or male or female patients of
reproductive potential who are not employing an effective method of birth
control.
* Serious preexisting medical or psychiatric conditions that, in the opinion of
the investigator, would preclude participation in the study.
* Chronic or active infection requiring systemic therapy, as well as a history
of symptomatic viral infection which has not been fully cured (eg, HIV or viral
hepatitis B or C).
* Symptomatic central nervous system (CNS) malignancy or metastasis. Screening
of asymptomatic patients without history of CNS metastases is not required.
* History of congestive heart failure with New York Heart Association class
greater than 2 (Class 1 and 2 are eligible), unstable angina (within 3 months
prior to study enrollment), recent myocardial infarction (within 6 months of
study enrollment), transient ischemic attacks, stroke, arterial or venous
vascular disease, or clinically significant symptomatic arrhythmia despite
anti-arrhythmic therapy.
* Corrected QT by Fridericia method interval >470 msec.
* Treatment with anticancer chemotherapy or biologic therapy or with an
experimental anticancer agent within 28 days of the initial dose of study drug.
* Patient has a history of severe allergic or anaphylactic reactions to
recombinant proteins or excipients used in TAK-164 or 89Zr-TAK-164 formulation.
* Patient has concurrent alcohol abuse or a history of drug-induced liver
injury (DILI).

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>Primary endpoints for this study are:<br /><br>* Number of patients with a DLT.<br /><br>* Percentage of patients with adverse events (AEs).<br /><br>* Percentage of patients with Grade 3 or above AEs.<br /><br>* Percentage of patients with drug-related AEs.<br /><br>* Percentage of patients with drug-related Grade 3 or above AEs.<br /><br>* Percentage of patients with serious adverse events.<br /><br>* Percentage of patients with AEs leading to discontinuation.<br /><br>* Percentage of participants who meet the markedly abnormal criteria for safety<br /><br>laboratory tests at least once postdose.<br /><br>* Percentage of participants who meet the markedly abnormal criteria for vital<br /><br>sign measurements at least once postdose.<br /><br>* MTD and/or an alternate RP2D of TAK-164.</p><br>

Secondary Outcome Measures

Name	Time	Method
<p>Secondary endpoints for this study are:<br /><br>* TAK-164 PK parameters: Cmax, tmax, and AUClast during Cycle 1 Day 1 and Cycle<br /><br>2 Day 1. In addition, observed concentration at the end of a dosing interval<br /><br>(Ctrough) may be reported for other dosing days during which a single predose<br /><br>PK sample is collected.<br /><br>* ORR as assessed per modified RECIST version 1.1.<br /><br>* DCR.<br /><br>* DOR.<br /><br>* PFS.<br /><br>* Antidrug antibody (ADA) in serum.<br /><br><br /><br>Imaging-specific secondary endpoints (Part C only):<br /><br>* Qualitative and quantitative (in terms of standardized uptake value [SUV])<br /><br>determination of patient-level biodistribution of 89Zr-TAK-164 at all<br /><br>89Zr-TAK-164 imaging time points.<br /><br>* Qualitative and quantitative (SUV) determination of 89Zr-TAK-164 uptake in<br /><br>tumor lesions identified with CT/18F-FDG-PET at all 89Zr imaging time points.</p><br>