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MLN0264 starting dose 0.3 mg/kg escalated until Maximum Tolerated Dose (MTD) was determined, 30-minute infusion, on Day 1 of each 21-Day treatment cycle.

MLN0264 30-minute infusion on Day 1 of each treatment cycle

MLN0264

Medical Monitor

This is an Open-Label, Multicenter, Dose Escalation, First-in-Human Study of MLN0264 in Adult Patients With Advanced Gastrointestinal Malignancies Expressing Guanylyl Cyclase C.

Phase 1 Study of MLN0264 in Adult Patients With Advanced Gastrointestinal Malignancies Expressing Guanylyl Cyclase C

An Open-Label, Dose Escalation, Phase 1, First-in-Human Study of MLN0264 in Adult Patients With Advanced Gastrointestinal Malignancies Expressing Guanylyl Cyclase C

DLT was defined as any of the following Adverse Events (AEs) that occur and are considered by the investigator to be related to therapy.

1. Grade 4 neutropenia (Absolute Neutrophil Count \< 500 cells/mm\^3).
2. Grade 3 or greater neutropenia with fever and/or infection.
3. Grade 4 thrombocytopenia (platelets \< 25,000/mm\^3).
4. Grade 3 or greater thrombocytopenia with clinically meaningful bleeding at any time.
5. Grade 3 or greater nausea and/or emesis that occurs despite of prophylaxis.
6. Grade 3 or greater diarrhea that occurs despite supportive care.
7. Any other Grade 3 or greater non-hematological toxicity other than Grade 3 fatigue or Grade 3 Alopecia.
8. Inability to start the next cycle of therapy due to treatment delay of more than 2 weeks because of lack of recovery.
9. Other MLN0264-related non-hematologic toxicities Grade 2 or greater requiring discontinuation of therapy.

An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug.

A Serious Adverse Event (SAE) was any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant.

A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.

MTD of MLN0264 was determined. Decisions regarding dose escalation were made based on any DLT that occurred during the first cycle of treatment.

Maximum observed serum concentration (Cmax) is the peak serum concentration of a drug after administration, obtained directly from the serum concentration-time curve. Cmax is reported for the 1.8 mg/kg dose, which is the MTD, where there is adequate data to provide robust parameter information reliably.

Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve. Cmax is reported for the 1.8 mg/kg dose, which is the MTD, where there is adequate data to provide robust parameter information reliably.

Area under the drug concentration versus time curve from time 0 to Day 21. AUC0-21 is reported for the 1.8 mg/kg dose (the MTD), where there is adequate data to provide robust parameter information reliably.

Area under the plasma drug concentration versus time curve from time 0 to Day 21. AUC0-21 is reported for the 1.8 mg/kg dose (the MTD), where there is adequate data to provide robust parameter information reliably.

The percentage of participants in each best overall response category, was determined using the Modified Response Evaluation Criteria in Solid Tumors (RECIST).

Complete Response: Disappearance of all target lesions and all non-target lesions and normalization of tumor marker level.

Partial Response: At least a 30% decrease in the sum of the Longest Diameter (LD) of target lesions, taking as reference the baseline sum LD.

Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the start or the appearance of one or more new lesions. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.

Stable Disease: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD. Persistence of one or more non-target lesion(s) or/and maintenance of tumor marker level above the normal limits.

Blood was collected and sent to a laboratory to determine the immunogenicity, whether binding antibodies to MLN0264 were present (ATA development).

Millennium Pharmaceuticals, Inc.

At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.

MLN0264 0.3 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, until disease progression or unacceptable toxicity or up to 1 year.

MLN0264 0.3 mg/kg

MLN0264 0.6 mg/kg, 30-minute intravenous IV infusion, Day 1 of each 21-day cycle, until disease progression or unacceptable toxicity or up to 1 year.

MLN0264 0.6 mg/kg

MLN0264 1.2 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, until disease progression or unacceptable toxicity or up to 1 year.

MLN0264 1.2 mg/kg

MLN0264 1.5 mg/kg, 30-minute intravenous IV infusion, Day 1 of each 21-day cycle, until disease progression or unacceptable toxicity or up to 1 year.

MLN0264 1.5 mg/kg

MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, until disease progression or unacceptable toxicity or up to 1 year.

MLN0264 1.8 mg/kg

MLN0264 2.1 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, until disease progression or unacceptable toxicity or up to 1 year.

MLN0264 2.1 mg/kg

MLN0264 2.4 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, until disease progression or unacceptable toxicity or up to 1 year.

MLN0264 2.4 mg/kg

All participants who participated in the Dose Escalation and mCRC Expansion Phases.

All Participants

Age, Continuous

Sex: Female, Male

Hispanic or Latino

Not Hispanic or Latino

Not Reported

Race/Ethnicity, Customized

White

Height data is only available for 39 participants.

Height

Weight

Body surface area data is only available for 39 participants.

Body Surface Area

Safety population included all participants who received at least 1 dose of study drug. A total of 41 participants participated in the study. There were 3 participants who participated in both phases of the study and are only counted once.

Medical Director, Clinical Science

DLT evaluable Population: participants enrolled in the Dose Escalation phase of the study who either experienced a DLT during Cycle 1 or received a scheduled Cycle 1 dose and completed all study procedures in Cycle 1 without DLT.

Number of Participants With Dose-Limiting Toxicities (DLTs)

Adverse Events

Serious Adverse Events

MLN0264 0.3 to 2.4 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, until disease progression or unacceptable toxicity or up to 1 year in the dose escalation phase.

MLN0264 Dose Escalation Phase

MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, until disease progression or unacceptable toxicity or up to 1 year in participants with metastatic colorectal (rectal, colon, or colorectal) cancer (mCRC).

MLN0264 1.8 mg/kg (mCRC Expansion)

Safety Analysis Set included all participants who received at least one dose of study drug.

Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events

Maximum Tolerated Dose (MTD) of MLN0264

Complete Response (CR)

Partial Response (PR)

CR + PR

Stable Disease

Progressive Disease

Response Evaluable Population is defined as patients with measureable disease who receive any amount of MLN0264 and have at least 1 post-Baseline response assessment.

Best Overall Response

Number of Participants With Antitherapeutic Antibodies (ATA)

Participants from the Pharmacokinetic (PK)-evaluable Population, all participants with sufficient dosing and reliable PK data to estimate PK parameters.

Cmax: Maximum Observed Serum Concentration for MLN0264

Cmax: Maximum Observed Plasma Concentration for Monomethyl Auristatin E (MMAE)

Participants from the PK-evaluable Population, all participants with sufficient dosing and reliable PK data to estimate PK parameters.

AUC0-21 Days: Area Under the Curve Day 0 to Day 21 for MLN0246

Participants from the PK-evaluable Population, all participants with sufficient dosing and reliable PK data to estimate PK parameter AUC0-21 days.

AUC0-21 Days: Area Under the Curve Day 0 to Day 21 for MMAE

Dose Escalation Phase

mCRC Expansion Phase

Antineoplastic Agents

Cetuximab

Antineoplastic Agents, Immunological

Tablets/IV, Oral/IV , Brivanib 800 mg + Erbitux 400 mg/m2 X 1, followed by 250mg/m2, Brivanib QD / Erbitux QW, up to 48 weeks

Brivanib + Cetuximab

Bristol-Myers Squibb

This is a phase I dose escalation study to determine the safety, pharmacokinetics and pharmacodynamics of BMS-582664 in combination with full dose erbitux in patients with advanced colorectal cancer who have received no more than 2 prior regimens for metastatic colorectal cancer.

BMS-582664 in Combination With Erbitux in Patients With Advanced Gastrointestinal Malignancies

Phase I Dose Escalation Study to Determine the Safety, Pharmacokinetics and Pharmacodynamics of BMS-582664 in Combination With Full Dose Erbitux in Patients With Advanced Gastrointestinal Malignancies Who Have Failed Prior Therapy

Study Director

Gemcitabine

Capecitabine

Oxaliplatin

Antimetabolites

Oxaliplatin 85 mg/m2 IV on days 1 and 15.

Gemcitabine 800 mg/m2 IV on days 1 and 15.

Capecitabine 600 mg/m2 BID orally on days 1-7 and days 15-21 rounded off to the nearest 150 mg or 500 mg tablet.

Each cycle is 28 days.

Oxaliplatin 100 mg/m2 IV on days 1 and 15.

Gemcitabine 800 mg/m2 IV on days 1 and 15.

Capecitabine 600 mg/m2 BID orally on days 1-7 and days 15-21 rounded off to the nearest 150 mg or 500 mg tablet.

Each cycle is 28 days.

Oxaliplatin 100 mg/m2 IV on days 1 and 15.

Gemcitabine 800 mg/m2 IV on days 1 and 15.

Capecitabine 800 mg/m2 BID orally on days 1-7 and days 15-21 rounded off to the nearest 150 mg or 500 mg tablet.

Each cycle is 28 days.

Oxaliplatin 100 mg/m2 IV on days 1 and 15.

Gemcitabine 1000 mg/m2 IV on days 1 and 15.

Capecitabine 800 mg/m2 BID orally on days 1-7 and days 15-21 rounded off to the nearest 150 mg or 500 mg tablet.

Each cycle is 28 days.

Benjamin Tan, M.D.

Dose escalation of oxaliplatin, gemcitabine and capecitabine in the treatment of patients with advanced gastrointestinal malignancies and other solid tumors.

To define the maximum tolerated dose of oxaliplatin, gemcitabine and capecitabine in the treatment of patients with advanced gastrointestinal malignancies and other solid tumors.

Study Of Advanced Gastrointestinal Malignancies And Other Solid Tumors

Phase I Study Of Oxaliplatin, Gemcitabine And Capecitabine In Advanced Gastrointestinal Malignancies And Other Solid Tumors

Washington University School of Medicine

Neoplasms

Symptoms and General Pathology

All Conditions

Digestive System Diseases

Neoplasm Metastasis

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Micronutrients

Irinotecan

Leucovorin

Fluorouracil

BMS-582664

The purpose of this study is to define the recommended dose of BMS-582664 that could be safely combined with 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) or 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy regimens in patients with advanced gastrointestinal malignancies and to evaluate the safety profile, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of these combinations.

Study of BMS-582664 in Combination With Either FOLFIRI or FOLFOX for Gastrointestinal (GI) Malignancies

A Phase I Study to Determine the Safety, Pharmacokinetics and Pharmacodynamics of BMS-582664 in Combination With 5-Fluorouracil/Leucovorin and Irinotecan or Oxaliplatin for Patients With Advanced or Metastatic Cancer

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Phase 1 Study of MLN0264 in Adult Patients With Advanced Gastrointestinal Malignancies Expressing Guanylyl Cyclase C	NCT01577758	Advanced Gastro...	MLN0264	18 Years -	Takeda
BMS-582664 in Combination With Erbitux in Patients With Advanced Gastrointestinal Malignancies	NCT00207051	Colorectal Canc...	Brivanib + Cetu...	18 Years -	Bristol-Myers Squibb
Study Of Advanced Gastrointestinal Malignancies And Other Solid Tumors	NCT00660426	Advanced Gastro... Solid Tumors	Oxaliplatin Gemcitabine Capecitabine	18 Years -	Washington University School of Medicine
Study of BMS-582664 in Combination With Either FOLFIRI or FOLFOX for Gastrointestinal (GI) Malignancies	NCT00300027	Gastrointestina...	BMS-582664	18 Years - 65 Years	Bristol-Myers Squibb
BMS-582664 in Combination With Erbitux in Patients With Advanced Gastrointestinal Malignancies	NCT00207051	Colorectal Canc...	Brivanib + Cetu...	18 Years -	Bristol-Myers Squibb

Spots Global Cancer Trial Database for advanced gastrointestinal malignancies