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

Study Overview
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Brief Summary
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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.

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

Conditions
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Advanced Gastrointestinal Malignancies

Intervention / Treatment
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* Drug: MLN0264


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Voluntary consent form Diagnosis of GI malignancy with a GCC protein expressing tumor Male or female patients 18 years or older with measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) Female patients who are post menopausal, surgically sterile, or agree to practice 2 effective methods of contraception or agree to abstain from heterosexual intercourse Male patients who agree to practice effective barrier contraception or agree to abstain from heterosexual intercourse Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Adequate bone marrow, hepatic and renal function as specified in the protocol Exclusion Criteria: Female patients who are lactating or have a positive serum pregnancy test during the screening period Any serious medical or psychiatric illness that could interfere with the completion of treatment Major surgery or treatment with investigational drug before the first dose Serious infection within 14 days before the first dose of study drug Known HIV, inflammatory bowel disease, viral hepatitis or cerebral/meningeal brain metastases Patients with cardiovascular conditions specified in protocols Patients with history of another primary malignancy not in remission for at least 3 years Please note that there are additional inclusion and exclusion criteria. The study center will determine if you meet all of the criteria. Site personnel will explain the trial in detail and answer any question you may have if you do qualify for the study. You can then decide whether or not you wish to participate. If you do not qualify for the trial, site personnel will explain the reasons.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MLN0264<br>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. | Drug: MLN0264<br>* MLN0264 30-minute infusion on Day 1 of each treatment cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose-Limiting Toxicities (DLTs) | DLT was defined as any of the following Adverse Events (AEs) that occur and are considered by the investigator to be related to therapy. Grade 4 neutropenia (Absolute Neutrophil Count < 500 cells/mm^3). Grade 3 or greater neutropenia with fever and/or infection. Grade 4 thrombocytopenia (platelets < 25,000/mm^3). Grade 3 or greater thrombocytopenia with clinically meaningful bleeding at any time. Grade 3 or greater nausea and/or emesis that occurs despite of prophylaxis. Grade 3 or greater diarrhea that occurs despite supportive care. Any other Grade 3 or greater non-hematological toxicity other than Grade 3 fatigue or Grade 3 Alopecia. Inability to start the next cycle of therapy due to treatment delay of more than 2 weeks because of lack of recovery. Other MLN0264-related non-hematologic toxicities Grade 2 or greater requiring discontinuation of therapy. | From the time informed consent is signed through 30 days after the last dose of study drug, approximately 9 months | 
| Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events | 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. | From the time informed consent is signed through 30 days after the last dose of study drug, approximately 9 months | 
| Maximum Tolerated Dose (MTD) of MLN0264 | MTD of MLN0264 was determined. Decisions regarding dose escalation were made based on any DLT that occurred during the first cycle of treatment. | Every 3 weeks until MTD is established, approximately 9 months | 
| Cmax: Maximum Observed Serum Concentration for MLN0264 | 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. | Cycle 1: Day 1 pre-dose to Day 21 post-dose | 
| Cmax: Maximum Observed Plasma Concentration for Monomethyl Auristatin E (MMAE) | 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. | Cycle 1: Day 1 pre-dose to Day 21 post-dose | 
| AUC0-21 Days: Area Under the Curve Day 0 to Day 21 for MLN0246 | 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. | Cycle 1: Day 1 pre-dose to 21 Days post-dose | 
| AUC0-21 Days: Area Under the Curve Day 0 to Day 21 for MMAE | 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. | Cycle 1: Day 1 pre-dose to 21 Days post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response | 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. | At the completion of every second cycle up to 12 cycles (approximately 9 months). Each cycle is a 21 days cycle | 
| Number of Participants With Antitherapeutic Antibodies (ATA) | Blood was collected and sent to a laboratory to determine the immunogenicity, whether binding antibodies to MLN0264 were present (ATA development). | Day 1 of every 21 days cycle and at End of study (EOS) approximately 9 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase 1,, Advanced gastrointestinal malignancies,, MLN0264,, Guanylyl Cyclase C(GCC),, Antibody Drug Conjugate(ADC)