Advanced Gastrointestinal Malignancies
Conditions
Keywords
Phase 1,, Advanced gastrointestinal malignancies,, MLN0264,, Guanylyl Cyclase C(GCC),, Antibody Drug Conjugate(ADC)
Brief summary
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.
Interventions
DRUGMLN0264
MLN0264 30-minute infusion on Day 1 of each treatment cycle
Sponsors
Millennium Pharmaceuticals, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC0-21 Days: Area Under the Curve Day 0 to Day 21 for MMAE | Cycle 1: Day 1 pre-dose to 21 Days post-dose | 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. |
| Cmax: Maximum Observed Plasma Concentration for Monomethyl Auristatin E (MMAE) | Cycle 1: Day 1 pre-dose to Day 21 post-dose | 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. |
| AUC0-21 Days: Area Under the Curve Day 0 to Day 21 for MLN0246 | Cycle 1: Day 1 pre-dose to 21 Days post-dose | 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. |
| Number of Participants With Dose-Limiting Toxicities (DLTs) | From the time informed consent is signed through 30 days after the last dose of study drug, approximately 9 months | 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. |
| Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events | From the time informed consent is signed through 30 days after the last dose of study drug, approximately 9 months | 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. |
| Maximum Tolerated Dose (MTD) of MLN0264 | Every 3 weeks until MTD is established, approximately 9 months | MTD of MLN0264 was determined. Decisions regarding dose escalation were made based on any DLT that occurred during the first cycle of treatment. |
| Cmax: Maximum Observed Serum Concentration for MLN0264 | Cycle 1: Day 1 pre-dose to Day 21 post-dose | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Antitherapeutic Antibodies (ATA) | Day 1 of every 21 days cycle and at End of study (EOS) approximately 9 months | Blood was collected and sent to a laboratory to determine the immunogenicity, whether binding antibodies to MLN0264 were present (ATA development). |
| Best Overall Response | At the completion of every second cycle up to 12 cycles (approximately 9 months). Each cycle is a 21 days cycle | 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. |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 4 investigative sites in the United States and Spain from 11 June 2012 to 12 February 2014.
Pre-assignment details
Participants with Gastrointestinal malignancies expressing guanylyl cyclase C were enrolled in the dose escalation phase: 0.3, 0.6, 1.2, 1.5, 1.8, 2.1 and 2.4 mg/kg to determine the maximum tolerated dose (MTD). MTD was established and participants were enrolled in the mCRC expansion phase. 3 participants were in both the 1.8 mg/kg and mCRC arms.
Participants by arm
| Arm | Count |
|---|---|
| All Participants All participants who participated in the Dose Escalation and mCRC Expansion Phases. | 41 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Dose Escalation Phase | Adverse Event | 0 | 0 | 0 | 0 | 0 | 2 | 1 | 0 |
| Dose Escalation Phase | Progression Disease | 2 | 2 | 1 | 2 | 5 | 0 | 0 | 0 |
| Dose Escalation Phase | Symptomatic Deterioration | 0 | 0 | 1 | 0 | 1 | 1 | 0 | 0 |
| Dose Escalation Phase | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| mCRC Expansion Phase | Progression Disease | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 19 |
| mCRC Expansion Phase | Symptomatic Deterioration | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 4 |
| mCRC Expansion Phase | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 58.7 years STANDARD_DEVIATION 10.81 |
| Body Surface Area | 1.929 m^2 STANDARD_DEVIATION 0.2424 |
| Height | 170.4 cm STANDARD_DEVIATION 7.69 |
| Race/Ethnicity, Customized Hispanic or Latino | 5 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 34 participants |
| Race/Ethnicity, Customized Not Reported | 2 participants |
| Race/Ethnicity, Customized White | 39 participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 27 Participants |
| Weight | 78.50 kg STANDARD_DEVIATION 18.573 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 2 | 2 / 2 | 2 / 2 | 2 / 2 | 28 / 28 | 4 / 4 | 1 / 1 |
| serious Total, serious adverse events | 0 / 2 | 2 / 2 | 1 / 2 | 0 / 2 | 10 / 28 | 2 / 4 | 1 / 1 |
Outcome results
Primary
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.
Time frame: Cycle 1: Day 1 pre-dose to 21 Days post-dose
Population: Participants from the PK-evaluable Population, all participants with sufficient dosing and reliable PK data to estimate PK parameters.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| MLN0264 0.3 mg/kg | AUC0-21 Days: Area Under the Curve Day 0 to Day 21 for MLN0246 | 67.81 day*μg/mL |
Primary
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.
Time frame: Cycle 1: Day 1 pre-dose to 21 Days post-dose
Population: Participants from the PK-evaluable Population, all participants with sufficient dosing and reliable PK data to estimate PK parameter AUC0-21 days.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| MLN0264 0.3 mg/kg | AUC0-21 Days: Area Under the Curve Day 0 to Day 21 for MMAE | 51.90 day*ng/mL |
Primary
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.
Time frame: Cycle 1: Day 1 pre-dose to Day 21 post-dose
Population: Participants from the Pharmacokinetic (PK)-evaluable Population, all participants with sufficient dosing and reliable PK data to estimate PK parameters.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| MLN0264 0.3 mg/kg | Cmax: Maximum Observed Plasma Concentration for Monomethyl Auristatin E (MMAE) | 7.91 ng/mL |
Primary
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.
Time frame: Cycle 1: Day 1 pre-dose to Day 21 post-dose
Population: Participants from the Pharmacokinetic (PK)-evaluable Population, all participants with sufficient dosing and reliable PK data to estimate PK parameters.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| MLN0264 0.3 mg/kg | Cmax: Maximum Observed Serum Concentration for MLN0264 | 48.63 μg/mL |
Primary
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.
Time frame: Every 3 weeks until MTD is established, approximately 9 months
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MLN0264 0.3 mg/kg | Maximum Tolerated Dose (MTD) of MLN0264 | 1.8 mg/kg |
Primary
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. 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.
Time frame: From the time informed consent is signed through 30 days after the last dose of study drug, approximately 9 months
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MLN0264 0.3 mg/kg | Number of Participants With Dose-Limiting Toxicities (DLTs) | 0 participants |
| MLN0264 0.6 mg/kg | Number of Participants With Dose-Limiting Toxicities (DLTs) | 0 participants |
| MLN0264 1.2 mg/kg | Number of Participants With Dose-Limiting Toxicities (DLTs) | 0 participants |
| MLN0264 1.5 mg/kg | Number of Participants With Dose-Limiting Toxicities (DLTs) | 0 participants |
| MLN0264 1.8 mg/kg | Number of Participants With Dose-Limiting Toxicities (DLTs) | 1 participants |
| MLN0264 2.1 mg/kg | Number of Participants With Dose-Limiting Toxicities (DLTs) | 2 participants |
| MLN0264 2.4 mg/kg | Number of Participants With Dose-Limiting Toxicities (DLTs) | 1 participants |
Primary
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.
Time frame: From the time informed consent is signed through 30 days after the last dose of study drug, approximately 9 months
Population: Safety Analysis Set included all participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MLN0264 0.3 mg/kg | Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events | Adverse Events | 19 participants |
| MLN0264 0.3 mg/kg | Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events | Serious Adverse Events | 8 participants |
| MLN0264 0.6 mg/kg | Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events | Adverse Events | 25 participants |
| MLN0264 0.6 mg/kg | Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events | Serious Adverse Events | 9 participants |
Secondary
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.
Time frame: At the completion of every second cycle up to 12 cycles (approximately 9 months). Each cycle is a 21 days cycle
Population: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MLN0264 0.3 mg/kg | Best Overall Response | Partial Response (PR) | 6 percentage of participants |
| MLN0264 0.3 mg/kg | Best Overall Response | Stable Disease | 39 percentage of participants |
| MLN0264 0.3 mg/kg | Best Overall Response | CR + PR | 6 percentage of participants |
| MLN0264 0.3 mg/kg | Best Overall Response | Progressive Disease | 56 percentage of participants |
| MLN0264 0.3 mg/kg | Best Overall Response | Complete Response (CR) | 0 percentage of participants |
| MLN0264 0.6 mg/kg | Best Overall Response | Progressive Disease | 58 percentage of participants |
| MLN0264 0.6 mg/kg | Best Overall Response | Complete Response (CR) | 0 percentage of participants |
| MLN0264 0.6 mg/kg | Best Overall Response | Partial Response (PR) | 0 percentage of participants |
| MLN0264 0.6 mg/kg | Best Overall Response | CR + PR | 0 percentage of participants |
| MLN0264 0.6 mg/kg | Best Overall Response | Stable Disease | 42 percentage of participants |
Secondary
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).
Time frame: Day 1 of every 21 days cycle and at End of study (EOS) approximately 9 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MLN0264 0.3 mg/kg | Number of Participants With Antitherapeutic Antibodies (ATA) | 0 participants |
| MLN0264 0.6 mg/kg | Number of Participants With Antitherapeutic Antibodies (ATA) | 0 participants |
| MLN0264 1.2 mg/kg | Number of Participants With Antitherapeutic Antibodies (ATA) | 0 participants |
| MLN0264 1.5 mg/kg | Number of Participants With Antitherapeutic Antibodies (ATA) | 0 participants |
| MLN0264 1.8 mg/kg | Number of Participants With Antitherapeutic Antibodies (ATA) | 0 participants |
| MLN0264 2.1 mg/kg | Number of Participants With Antitherapeutic Antibodies (ATA) | 0 participants |
| MLN0264 2.4 mg/kg | Number of Participants With Antitherapeutic Antibodies (ATA) | 0 participants |
| MLN0264 1.8 mg/kg (mCRC Expansion) | Number of Participants With Antitherapeutic Antibodies (ATA) | 0 participants |