Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Dalotuzumab · 7 trials · 8 indications
A DLT was an AE related (definitely, probably, or possibly) to study therapy and occurring within first 4 weeks of therapy. Hematologic DLTs included Grade (Gr)4 neutropenia lasting for ≥7 days, Gr 3/Gr 4 neutropenia with fever \>38.5 °C and/or infection requiring antibiotic or anti-fungal treatment, and Gr 4 thrombocytopenia (25.0 x 10\^9/L). Non-hematologic DLT defined as any ≥Gr 3 nonhematologic toxicity, except Gr 3 reversible rash; Gr 3 nausea, vomiting, diarrhea, dehydration, or hyperglycemia occurring in setting of inadequate compliance with supportive care; alopecia; anorexia; asthenia; inadequately-treated hypersensitivity reactions; Gr 3 elevated transaminases (≤1 week duration); or infusion reactions to dalotuzumab. Any drug-related AEs that led to dose modification of dalotuzumab/erlotinib or any unresolved drug-related toxicity that caused a ≥3 week delay of next scheduled dose of study drug, regardless of Common Terminology Criteria grade, were DLTs.
PFS was defined as the time from randomization until either the emergence of radiographic evidence of disease progression or death due to any cause, whichever occurs first. Disease progression was classified as a radiographic assessment of progressive disease (PD) according to Response Evaluation Criteria in Solid Tumors (RECIST) using computed tomography (CT) or magnetic resonance imaging (MRI). As pre-specified by the protocol, final analysis of PFS was to take place after approximately 49 PFS events or deaths had occurred in the Phase II part of the trial. A non-parametric Kaplan-Meier method was used to estimate the median PFS time for each treatment group. Participants who discontinued from the study for reasons other than progression of disease were treated as right-censored observations at the time of the last response evaluation. Participants who withdrew from the study due to PD were considered to have a disease progression between the last visit and the time of withdrawal.
The OS of participants with metastatic colorectal cancer (CRC) expressing the KRAS wild-type (wtKRAS) tumor genotype (indicating no detection of KRAS mutation) was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. OS was analyzed using the Kaplan-Meier method and is reported in months.
The PFS of participants with metastatic CRC expressing the wtKRAS genotype was defined as the time from the first day of study treatment to the first documented disease progression per Response Evaluation Criteria in Solid Tumors version 1.0 (RECIST 1.0) as documented by an independent core laboratory, or death due to any cause, whichever occurred first. Disease progression was defined as either a 20% or greater relative increase in the sum of diameters of target lesions OR an absolute increase of at least 5mm in the sum of lesions or the appearance of new lesions. PFS was analyzed using the Kaplan-Meier method and is reported in months.
An adverse event (AE) was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medical treatment or procedure that may or may not be considered related to the medical treatment or procedure. (Grade 3=Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4=Life-threatening consequences; urgent intervention indicated. Grade 5=Death related to AE.) Participants were monitored for AEs until the earlier of study discontinuation or 30 days after dalotuzumab/placebo discontinuation. AE grades were assessed using the National Cancer Institute (NCI) CTCAE, version 3.0.
An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medical treatment or procedure that may or may not be considered related to the medical treatment or procedure. (Grade 3=Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4=Life-threatening consequences; urgent intervention indicated. Grade 5=Death related to AE.) Drug-related AEs were those AEs that were possibly, probably, or definitely related to study drug or protocol-specified procedures. Participants were monitored for AEs related to dalotuzumab or placebo until the earlier of study discontinuation or 30 days after dalotuzumab/placebo discontinuation. AE grades were assessed using the NCI CTCAE, version 3.0.
An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medical treatment or procedure that may or may not be considered related to the medical treatment or procedure. The percentage of participants who discontinued study drug due to an AE is presented.
The percentage of participants who experienced an AE of infusion site reaction is presented.
GFS was measured by microarray analysis of the entire 101 gene signature expression. The GFS is quantified as the change in gene expression between two separate samples collected from the same participant. A log (base 10) ratio of expression in the post-dose sample was generated relative to the reference in both the Up and DOWN arms of the gene signature. A log ratio value of zero indicated no change in the expression between the two samples. GFS was calculated as the mean log ratio of genes in the UP arm minus mean log ratio of genes in the Down arm. GFS was compared for paired samples (pre-dose and post-dose) by a T-statistic calculated as the GFS divided by its standard error. Responders to therapy had a T-statistic that was smaller than the threshold 1st percentile of student's T-distribution and were counted as having a decrease in GFS.
Toxicity was graded and recorded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. DLTs were defined as the occurrence of any of the following events when judged to be related to the study medication: Grade 4 neutropenia; Grade 3 neutropenia with fever \>38.5°C; Grade 4 thrombocytopenia; Grade 3 or Grade 4 non-hematologic toxicity, except alopecia and inadequately treated diarrhea, nausea and vomiting. The number of participants who experienced a DLT is presented.
An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study treatment, whether or not considered related to the use of study treatment. Any worsening (i.e. any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition which was temporally associated with the use of study treatment, was also an AE. The number of participants who experienced at least one AE is presented.
An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study treatment, whether or not considered related to the use of study treatment. Any worsening (i.e. any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition which was temporally associated with the use of study treatment, was also an AE. The number of participants who discontinued study treatment due to an AE is presented.
Blood samples were obtained for analysis of steady-state serum concentration of dalotuzumab at 336 hours (C336) after the first maintenance dose of dalotuzumab. The C336 of dalotuzumab after intravenous administration is presented.
Dose-limiting toxicities (DLT) were assessed and graded using the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE). A DLT was defined as the occurrence of any of the following events, that were judged by the study investigator, to be related to the study medication: Grade 4 neutropenia; Grade 3 neutropenia with fever \>38.5 degrees Celsius; Grade 4 thrombocytopenia; Grade 3 or Grade 4 non-hematologic toxicity (except alopecia and inadequately treated diarrhea, nausea, and vomiting, and hyperglycemia lasting less than 5 days; and Grade 3 or greater hyperglycemia lasting for more than 5 days in spite of optimal medical management.
Toxicity was graded and recorded according to National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events version 3.0 (CTCAE 3.0). A DLT was defined as any Grade 3 or 4 toxicity. A Grade 3 toxicity was defined as severe or medically significant but not immediately life-threatening OR hospitalization or prolongation of hospitalization indicated OR disabling OR limiting self care activities of daily living. A Grade 4 toxicity was defined as: life-threatening consequences OR urgent intervention indicated. Participants were monitored for the occurrence of DLTs during the first 3 weeks of dosing with dalotuzumab.
Terminal half-life is defined as the time it takes for the blood plasma concentration of a substance to halve (plasma half-life). Blood samples for measurement of serum levels of dalotuzumab were obtained at: pre-dose; pre-end infusion; 0.5, 5, 10, 24, 30 (Q1W only), 48, 96, 168 (Q2W/Q3W only), 336 (Q3W only) hours post infusion. For infusions \>1 hour in duration, an additional sample was obtained at the mid-point of the infusion. Data presented are for the harmonic mean t1/2 for dalotuzumab.
AUC0-∞ represents the total drug exposure over time. Blood samples for measurement of serum levels of dalotuzumab were obtained at: Predose; pre-end infusion; 0.5, 5, 10, 24, 30 (Q1W only), 48, 96, 168 (Q2W/Q3W only), 336 (Q3W only) hours post-infusion. For infusions \>1 hour in duration, an additional sample was obtained at the mid-point of the infusion.
Clearance is defined as the volume of serum from which study drug was completely removed per unit of time. Blood samples for measurement of serum levels of dalotuzumab were obtained at: pre-dose; pre-end infusion; 0.5, 5, 10, 24, 30 (Q1W only), 48, 96, 168 (Q2W/Q3W only), 336 (Q3W only) hours post infusion. For infusions \>1 hour in duration, an additional sample was obtained at the mid-point of the infusion.
The lowest (trough) concentration of dalotuzumab prior to the next dose of dalotuzumab was measured.
| Arm | Type | Description |
|---|---|---|
| Ph I: Dalotuzumab 5 mg/kg + Erlotinib | EXPERIMENTAL | During the Phase I part of the study, participants receive dalotuzumab intravenously (IV) at 5 mg/kg weekly plus open-label erlotinib at 150 mg daily for 4 weeks. After 4 weeks of therapy, participants in Phase I who do not have disease progression and are satisfactorily tolerating study drug can continue to receive study drug. |
| Ph I: Dalotuzumab 10 mg/kg + Erlotinib | EXPERIMENTAL | During the Phase I part of the study, participants receive dalotuzumab intravenously (IV) at 10 mg/kg weekly plus open-label erlotinib at 150 mg daily for 4 weeks. After 4 weeks of therapy, participants in Phase I who do not have disease progression and are satisfactorily tolerating study drug can continue to receive study drug. |
| Ph II: Dalotuzumab 10 mg/kg + Erlotinib | EXPERIMENTAL | During the Phase II part of the study, participants are randomized to receive dalotuzumab intravenously (IV) at 10 mg/kg weekly plus open-label erlotinib at 150 mg daily until disease progression or occurrence of unacceptable toxic effects. |
| Ph II: Erlotinib | ACTIVE_COMPARATOR | During the Phase II part of the study, participants are randomized to receive open-label erlotinib at 150 mg daily until disease progression or occurrence of unacceptable toxic effects. |
| Dalotuzumab 10 mg/kg Q1W (DB) | EXPERIMENTAL | In double-blind (DB) Week 1, participants receive cetuximab 400 mg/m\^2 intravenously (IV) loading dose and irinotecan IV at their pre-study dosage. Starting with DB Week 2, participants receive cetuximab 250 mg/m\^2 IV one time each week (Q1W) maintenance dose, irinotecan IV Q1W and DB dalotuzumab 10 mg/kg IV Q1W for up to 32 months of treatment. |
| Dalotuzumab 15 mg/kg/7.5 mg/kg Q2W (OL) | EXPERIMENTAL | In the open-label (OL) portion of the study, ≥6 participants receive cetuximab 400 mg/m\^2 Q1W + irinotecan Q1W at their pre-study dosage + OL dalotuzumab (loading dose of 15 mg/kg IV followed by a maintenance dose of 7.5 mg/kg 2 weeks later) to verify the safety of the regimen. In DB Week 1, participants receive cetuximab 400 mg/m\^2 IV + irinotecan IV. In DB Week 2, participants receive cetuximab 250 mg/m\^2 IV + irinotecan IV + DB dalotuzumab 15 mg/kg IV. In DB Week 3, participants receive cetuximab 250 mg/m\^2 IV + irinotecan IV. Starting with DB Week 4, participants receive cetuximab 250 mg/m\^2 IV Q1W + irinotecan IV Q1W + DB dalotuzumab 7.5 mg/kg IV Q2W for up to 32 months of treatment. |
| Dalotuzumab 10 mg/kg Q1W (OL) | EXPERIMENTAL | In the OL portion of the study, ≥6 participants receive cetuximab 400 mg/m\^2 Q1W+ irinotecan Q1W at their pre-study dosage + OL dalotuzumab 10 mg/kg IV Q1W to verify the safety of the regimen. In DB Week 1, participants receive cetuximab 400 mg/m\^2 IV + irinotecan IV at their pre-study dosage. Starting with DB Week 2, participants receive cetuximab 250 mg/m\^2 IV Q1W + irinotecan IV Q1W + DB dalotuzumab 10 mg/kg IV Q1W for up to 32 months of treatment. |
| Dalotuzumab 15 mg/kg/7.5 mg/kg Q2W (DB) | EXPERIMENTAL | In DB Week 1, participants receive cetuximab 400 mg/m\^2 IV + irinotecan IV at their pre-study dosage. In DB Week 2, participants receive cetuximab 250 mg/m\^2 IV + irinotecan IV + DB dalotuzumab 15 mg/kg IV. In DB Week 3, participants receive cetuximab 250 mg/m\^2 IV + irinotecan IV. Starting with DB Week 4, participants receive cetuximab 250 mg/m\^2 IV Q1W + irinotecan IV Q1W + DB dalotuzumab 7.5 mg/kg IV Q2W for up to 32 months of treatment. |
| Placebo + Cetuximab + Irinotecan (DB) | ACTIVE_COMPARATOR | In DB Week 1, participants receive cetuximab 400 mg/m\^2 IV + irinotecan IV at their pre-study dosage. Starting with DB Week 2, participants receive cetuximab 250 mg/m\^2 IV Q1W + irinotecan IV Q1W + DB normal saline (placebo) IV Q1W for up to 32 months of treatment. |
| Part 1: Dalotuzumab | EXPERIMENTAL | - |
| Parts 2 and 3: Dalotuzumab + ridaforolimus | EXPERIMENTAL | - |
| ER-positive Luminal B | EXPERIMENTAL | Single dose of dalotuzumab 20 mg/kg infused intravenously over 60-120 minutes. |
| Triple Negative | EXPERIMENTAL | Single dose of dalotuzumab 20 mg/kg infused intravenously over 60-120 minutes. |
| Dalotuzumab 5 mg/kg | EXPERIMENTAL | Participants receive dalotuzumab 5 mg/kg by intravenous (IV) infusion once each week for up to 1 year or until participant withdraws consent, experiences an adverse event (AE), progressive disease or major protocol violation, has moved or is lost to follow up. |
| Dalotuzumab 10 mg/kg | EXPERIMENTAL | Participants receive dalotuzumab 10 mg/kg by IV infusion once each week for up to 1 year or until participant withdraws consent, experiences an AE, progressive disease or major protocol violation, has moved or is lost to follow up. |
| Dalotuzumab 15 mg/kg/7.5 mg/kg | EXPERIMENTAL | Participants receive an initial dose of dalotuzumab 15 mg/kg by IV infusion followed by a maintenance dose of dalotuzumab 7.5 mg/kg by IV infusion once every 2 weeks for up to 1 year or until participant withdraws consent, experiences an AE, progressive disease or major protocol violation, has moved or is lost to follow up. |
| dalotuzumab 2.5/2.5 mg/kg | EXPERIMENTAL | Participants received a loading dose of dalotuzumab 2.5 mg/kg administered by intravenous (IV) infusion. Two weeks following completion of the loading dose, participants received a maintenance dose of dalotuzumab 2.5 mg/kg administered by IV infusion every two weeks for up to 18 months. |
| dalotuzumab 5.0/5.0 mg/kg | EXPERIMENTAL | Participants received a loading dose of dalotuzumab 5.0 mg/kg administered by IV infusion. Two weeks following completion of the loading dose, participants received a maintenance dose of dalotuzumab 5.0 mg/kg administered by IV infusion every two weeks for up to 18 months. |
| dalotuzumab 10.0/5.0 mg/kg | EXPERIMENTAL | Participants received a loading dose of dalotuzumab 10.0 mg/kg administered by IV infusion. Two weeks following completion of the loading dose, participants received a maintenance dose of dalotuzumab 5.0 mg/kg administered by IV infusion every two weeks for up to 18 months. |
| dalotuzumab 15.0/5.0mg/kg | EXPERIMENTAL | Participants received a loading dose of dalotuzumab 15.0 mg/kg administered by IV infusion. Two weeks following completion of the loading dose, participants received a maintenance dose of dalotuzumab 5.0 mg/kg administered by IV infusion every two weeks for up to 18 months. |
| dalotuzumab 20.0/5.0 mg/kg | EXPERIMENTAL | Participants received a loading dose of dalotuzumab 20.0 mg/kg administered by IV infusion. Two weeks following completion of the loading dose, participants received a maintenance dose of dalotuzumab 5.0 mg/kg administered by IV infusion every two weeks for up to 18 months. |
| dalotuzumab 15.0/10.0 mg/kg | EXPERIMENTAL | Participants received a loading dose of dalotuzumab 15.0 mg/kg administered by IV infusion. Two weeks following completion of the loading dose, participants received a maintenance dose of dalotuzumab 10.0 mg/kg administered by IV infusion every two weeks for up to 18 months. |
| dalotuzumab 15.0/15.0 mg/kg | EXPERIMENTAL | Participants received a loading dose of dalotuzumab 15.0 mg/kg administered by IV infusion. Two weeks following completion of the loading dose, participants received a maintenance dose of dalotuzumab 15.0 mg/kg administered by IV infusion every two weeks for up to 18 months. |
| Dalotuzumab 1.25 mg/kg Q1W (10 mg/mL) | EXPERIMENTAL | Participants received dalotuzumab 1.25 mg/kg (10 mg/mL) intravenous (IV) infusion 1 time every 1 week (Q1W). |
| Dalotuzumab 2.5 mg/kg Q1W (10 mg/mL) | EXPERIMENTAL | Participants received dalotuzumab 2.5 mg/kg (10 mg/mL) IV infusion Q1W. |
| Dalotuzumab 5 mg/kg Q1W (10 mg/mL) | EXPERIMENTAL | Participants received dalotuzumab 5 mg/kg (10 mg/mL) IV infusion Q1W. |
| Dalotuzumab 10 mg/kg Q1W (10 mg/mL) | EXPERIMENTAL | Participants received dalotuzumab 10 mg/kg (10 mg/mL) IV infusion Q1W. |
| Dalotuzumab 10 mg/kg Q1W (20 mg/mL) | EXPERIMENTAL | Participants received dalotuzumab 10 mg/kg (20 mg/mL) IV infusion Q1W. |
| Dalotuzumab 15 mg/kg Q1W (10 mg/mL) | EXPERIMENTAL | Participants received dalotuzumab 15 mg/kg (10 mg/mL) IV infusion Q1W. |
| Dalotuzumab 15 mg/kg Q1W (20 mg/mL) | EXPERIMENTAL | Participants received dalotuzumab 15 mg/kg (20 mg/ mL) IV infusion Q1W. |
| Dalotuzumab 20 mg/kg Q1W (10 mg/mL) | EXPERIMENTAL | Participants received dalotuzumab 20 mg/kg (10 mg/mL) IV infusion Q1W. |
| Dalotuzumab 20 mg/kg Q1W (20 mg/mL) | EXPERIMENTAL | Participants received dalotuzumab 20.0 mg/kg (20 mg/mL) IV infusion Q1W. |
| Dalotuzumab 20 mg/kg Q2W (20 mg/mL) | EXPERIMENTAL | Participants received dalotuzumab 20 mg/kg (20 mg/mL) IV infusion 1 time every 2 weeks (Q2W). |
| Dalotuzumab 30 mg/kg Q3W (20 mg/mL) | EXPERIMENTAL | Participants received dalotuzumab 30 mg/kg (20 mg/mL) IV infusion1 time every 3 weeks (Q3W). |
| Name | Type | Description |
|---|---|---|
| Dalotuzumab | DRUG | Dalotuzumab 20 mg/mL in sterile solution. Intravenous (IV) infusion over 60 minutes at 5 mg/kg, administered weekly at dosage according to treatment group. |
| Erlotinib | DRUG | Open-label erlotinib administrated orally (tablets) by mouth (PO) at 150 mg daily. |
| irinotecan hydrochloride | DRUG | IV infusion |
| cetuximab | BIOLOGICAL | IV infusion |
| placebo | DRUG | IV infusion |
| ridaforolimus | DRUG | For Part 2: ridaforolimus 10 mg enteric coated tablets, orally, on 5 consecutive days each week, dose based on participant BSA, at 1 dose level lower than the MTD or highest dose level used in the companion study MK-8669-056. For Part 3:ridaforolimus 10 mg enteric coated tablets, orally, on 5 consecutive days each week, dose based on participant BSA, at the dose level identified for combination therapy in Part 2 |
| dalotuzumab (MK0646) | DRUG | Single intravenous infusion |
Inclusion Criteria: * Participant has locally advanced or metastatic stage IIIB/IV NSCLC that has relapsed after hemotherapy/chemoratiotherapy * Participant has had at least one chemotherapy regimen for recurrent or metastatic disease * Participant is 18 years of age or older * Participant has a pe...
Dalotuzumab is an investigational oncology drug being studied for use in several cancer types, including advanced solid tumors, metastatic colorectal cancer, non-small-cell lung carcinoma, and other neoplasms. It is currently in Phase 2 clinical development and has not been approved by regulatory authorities.
Dalotuzumab is a monoclonal antibody that targets the insulin-like growth factor 1 receptor (IGF-1R). By binding to this receptor, it is designed to interfere with cancer cell growth and survival pathways. This mechanism is being evaluated in clinical trials for various solid tumors.
Dalotuzumab is being developed by Merck & Company, Inc., a pharmaceutical company traded on the New York Stock Exchange under the ticker symbol MRK. The drug is currently in Phase 2 clinical trials for oncology indications.
Dalotuzumab is in Phase 2 clinical development. It is an investigational drug, meaning it has not been approved by the FDA or other regulatory agencies. Clinical trials are ongoing to evaluate its safety and efficacy in treating various types of cancer.
Dalotuzumab has been studied in several clinical trials, including NCT00614393, a Phase 2 study in metastatic colorectal cancer combining it with cetuximab and irinotecan, which enrolled 558 participants. Other completed Phase 1 trials include NCT00701103 in advanced solid tumors and multiple myeloma, NCT00759785 in breast cancer, and NCT00925015 in colorectal cancer.
Yes, Dalotuzumab is also known as MK-0646. Clinical trial records refer to the drug by both names, such as in the study titles 'Study of Dalotuzumab (MK-0646) in Combination With Cetuximab and Irinotecan in Metastatic Colorectal Cancer (MK-0646-004)' and other trials.