Neoplasms, Tumor
Conditions
Keywords
Advanced Solid Tumors
Brief summary
A study to evaluate the safety and tolerability of anti-TGFβRII monoclonal antibody (IMC-TR1) in participants with advanced solid tumors, as well as gather evidence of anti-tumor activity.
Detailed description
This is the first-in-human Phase 1 study of IMC-TR1.
Interventions
BIOLOGICALIMC-TR1
Administered intravenously
Sponsors
Eli Lilly and Company
Study design
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Part A and Part B: Participants must be appropriate candidates for experimental therapy, with a solid tumor that has failed standard therapy or for which no standard therapy is available, and evidence of progressive disease * Part A only: Participants must have histological or cytological evidence of a solid tumor which is advanced and/or metastatic * Part B only: Participants who have failed first-line therapy/standard of care and have histological or cytological evidence of a cancer type for which evidence of activity was observed during Part A or for which preclinical evidence of potential activity has been observed * Have the presence of measurable or nonmeasurable disease as defined by the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1) * Part A only: Participants may have measurable or nonmeasurable disease * Part B: Participants must have measurable disease * Have adequate organ function including: Hematologic, Hepatic, Albumin, Coagulation and Renal function * Have a performance status of ≤ 1 on the Eastern Cooperative Oncology Group (ECOG) scale * Have discontinued previous treatments for cancer and recovered from the acute effects of therapy * Males and females with reproductive potential must agree to use medically approved contraceptive precautions during the study and for 3 months following the last dose of study drug * Females with child bearing potential must have had a negative serum pregnancy test and must not be breastfeeding * Have an estimated life expectancy that is \> 3 months
Exclusion criteria
* Have clinically significant cardiac disease, including: * Myocardial infarction within 6 months prior to study entry, unstable angina pectoris, congestive heart failure, or uncontrolled hypertension * Major electrocardiogram (ECG) abnormalities * Major abnormalities documented by echocardiography with Doppler * Have known predisposing conditions that are consistent with development of aneurysms of the ascending aorta or aortic stress * Have Corrected QT Interval (QTc interval) of \> 500 msec on screening ECG * Have other known serious pre-existing medical conditions * Have received prior investigational therapy targeting Transforming growth factor beta (TGFβ) or its receptors * Have a known sensitivity to monoclonal antibodies or other therapeutic proteins, to agents of similar biologic composition as IMC-TR1 * Have a high risk of gastrointestinal bleeding, active inflammatory bowel disease, or chronic steroid use * Are currently using or has received a systemic thrombolytic agent within 28 days prior to enrollment * Are receiving: * full-dose warfarin * intravenous heparin or low-molecular-weight heparin * chronic daily treatment with aspirin at a dose greater than 325 mg per day or nonsteroidal anti-inflammatory medications known to inhibit platelet function * Have evidence of retinal disease or are a monocular participant * Have received a solid organ transplant, bone marrow transplant or stem cell transplant * Have symptomatic central nervous system (CNS) malignancy or untreated metastasis * Have acute or chronic leukemia * Have a known active fungal, bacterial, and/or viral infection including human immunodeficiency virus or viral hepatitis requiring treatment * Has a positive fecal occult blood test within 14 days prior to enrollment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose-Limiting Toxicities (DLTs) | First Dose Up to 6 Weeks | A DLT was defined as an AE occurring during Cycle 1(first 6 weeks of treatment) that was considered at least possibly related to study drug, was considered dose-dependent, and fulfilled a criteria selected (using the National Cancer Institute Common Terminology Criteria for Adverse Events,version 4.0 \[NCI-CTCAE v 4.0\] \[NCI 2009\]):Grade(Gr)≥3 nonhematological toxicity,Gr4 thrombocytopenia lasting at least 5 days and/or complicated with bleeding,Gr≥3 febrile neutropenia(ntr),Gr4 ntr of \>5 days' duration,increase(incr)of at least 1 gr from a preexisting Gr1 valvular insufficiency or any new Gr≥2 valvular toxicity,left ventricular(vtr) ejection fraction decrease of 10% in absolute value or 16% in relative value,incr in right vtr systolic pressure dysfunction from mild to moderate(mod) or from mod to severe,incr in left atrial or ventricular chamber size of ≥2 cm and ≥1cm respectively,any other life-threatening toxicity,significant morphologic on cardiac echocardiogram,any major ocular. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Immunogenicity - Development of Antibodies Against IMC-TR1 | Cycle 1 - Day 1 and Day 29, Cycle 2 - Day 15, Cycle 3 and Each Consecutive Cycle - Day 1 | — |
| Maximum Tolerated Dose (MTD) of IMC-TR1 | First Dose through Cycle 1 (6 Weeks) | The MTD was defined as the highest dose level at which ≤33% of participants experienced a DLT during Cycle 1. |
| Maximum Tolerated Dose (MTD) of IMC-TR1 (1.25 mg/kg LY3022859 ) for Participants Receiving a Weight-Based Dose | First Dose through Cycle 1 (6 Weeks) | The MTD was defined as the highest dose level at which ≤33% of participants experienced a DLT during Cycle 1. |
| Number of Dose-Limiting Toxicities (DLTs) | First Dose through Cycle 1 (6 Weeks) | — |
| Pharmacokinetics (PK) - Area Under the Concentration-time Curve (AUC[0-tlast]) and AUCτ of IMC-TR1 | Cycle (C) 1 Day (D) 1: 1, 2, 4, 8 hours (h); C1 D2: 24 h; C1 D3: 48 h; C1 D5: 96 h; C1 D8: 168 h; C1 D15: 336 h; C2 D15: 1, 2, 4, 8 h; C2 D16: 24 h; C2 D17: 48 h; C2 D19: 96 h; C2 D22: 168 h, C2 D29: 336 h | AUC (0-tlast) is area under the concentration versus time curve from the time zero to tlast. AUCτ is area under the concentration versus time curve during 1 dose interval (336 hours). |
| Pharmacokinetics - Maximum Concentration (Cmax) of IMC-TR1 | Cycle (C) 1 Day (D) 1: 1, 2, 4, 8 hours (h); C1 D2: 24 h; C1 D3: 48 h; C1 D5: 96 h; C1 D8: 168 h; C1 D15: 336 h; C2 D15: 1, 2, 4, 8 h; C2 D16: 24 h; C2 D17: 48 h; C2 D19: 96 h; C2 D22: 168 h, C2 D29: 336 h | — |
| Pharmacokinetics - Minimum Concentration (Cmin) of IMC-TR1 | Cycle 2 Day 1: Prior to fourth infusion 0 hour (h) | Pharmacokinetics - Minimum concentration (Cmin) of IMC-TR1 |
| Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR) (Overall Response Rate [ORR]) (Antitumor Activity of IMC-TR1 as Monotherapy, Assessed Via Tumor Measurement by Response Evaluation Criteria in Solid Tumors, Version 1.1) | First Dose to Measured Progressive Disease (Up To 21.3 Weeks) | ORR is the best response of CR or PR as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST v1.1). CR is a disappearance of all target and non-target lesions and normalization of tumor marker level. PR is an at least 30% decrease in the sum of the diameters of target lesions (taking as reference the baseline sum diameter) without progression of not-target lesions or appearance of new lesions. Overall response rate is calculated as a total number of participants with CR or PR divided by the total number of participants with at least 1 measurable lesion, multiplied by 100. |
Countries
United States
Participant flow
Pre-assignment details
Participants that completed Cohort 1A, Cohort 1B or Cohort 2 are those who died, had progressive disease (PD) or off treatment & censored due to study completion.
Participants by arm
| Arm | Count |
|---|---|
| 1.25 mg/kg LY3022859 Cohort 1A: 1.25 milligram/kilogram (mg/kg) LY3022859 administered intravenously (IV) once every 2 weeks (Q2W) during 6-week treatment cycles. | 2 |
| 12.5 mg LY3022859 Cohort 1B: 12.5 mg IV once Q2W during 6-week treatment cycles. | 5 |
| 25 mg LY3022859 Cohort 2: 25 mg IV once Q2W during 6-week treatment cycles. | 7 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 | 1 |
| Overall Study | Physician's Decision | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | 1.25 mg/kg LY3022859 | Total | 25 mg LY3022859 | 12.5 mg LY3022859 |
|---|---|---|---|---|
| Age, Continuous | 65.5 years STANDARD_DEVIATION 19.09 | 59.1 years STANDARD_DEVIATION 14.31 | 55.0 years STANDARD_DEVIATION 16.8 | 62.2 years STANDARD_DEVIATION 9.44 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 3 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 11 Participants | 7 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 14 Participants | 7 Participants | 5 Participants |
| Region of Enrollment United States | 2 participants | 14 participants | 7 participants | 5 participants |
| Sex: Female, Male Female | 0 Participants | 3 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 2 Participants | 11 Participants | 6 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 2 | 4 / 5 | 7 / 7 |
| serious Total, serious adverse events | 0 / 2 | 2 / 5 | 4 / 7 |
Outcome results
Primary
Number of Participants With Dose-Limiting Toxicities (DLTs)
A DLT was defined as an AE occurring during Cycle 1(first 6 weeks of treatment) that was considered at least possibly related to study drug, was considered dose-dependent, and fulfilled a criteria selected (using the National Cancer Institute Common Terminology Criteria for Adverse Events,version 4.0 \[NCI-CTCAE v 4.0\] \[NCI 2009\]):Grade(Gr)≥3 nonhematological toxicity,Gr4 thrombocytopenia lasting at least 5 days and/or complicated with bleeding,Gr≥3 febrile neutropenia(ntr),Gr4 ntr of \>5 days' duration,increase(incr)of at least 1 gr from a preexisting Gr1 valvular insufficiency or any new Gr≥2 valvular toxicity,left ventricular(vtr) ejection fraction decrease of 10% in absolute value or 16% in relative value,incr in right vtr systolic pressure dysfunction from mild to moderate(mod) or from mod to severe,incr in left atrial or ventricular chamber size of ≥2 cm and ≥1cm respectively,any other life-threatening toxicity,significant morphologic on cardiac echocardiogram,any major ocular.
Time frame: First Dose Up to 6 Weeks
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 1.25 mg/kg LY3022859 | Number of Participants With Dose-Limiting Toxicities (DLTs) | 2 Participants |
| 12.5 mg LY3022859 | Number of Participants With Dose-Limiting Toxicities (DLTs) | 0 Participants |
| 25 mg LY3022859 | Number of Participants With Dose-Limiting Toxicities (DLTs) | 2 Participants |
Secondary
Immunogenicity - Development of Antibodies Against IMC-TR1
Time frame: Cycle 1 - Day 1 and Day 29, Cycle 2 - Day 15, Cycle 3 and Each Consecutive Cycle - Day 1
Population: Zero participants were analyzed. Immunogenicity data were not collected.
Secondary
Maximum Tolerated Dose (MTD) of IMC-TR1
The MTD was defined as the highest dose level at which ≤33% of participants experienced a DLT during Cycle 1.
Time frame: First Dose through Cycle 1 (6 Weeks)
Population: All participants who received at least one dose of study drug and completed cycle 1 or discontinued treatment due to a DLT during the cycle 1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1.25 mg/kg LY3022859 | Maximum Tolerated Dose (MTD) of IMC-TR1 | NA milligram (mg) |
Secondary
Maximum Tolerated Dose (MTD) of IMC-TR1 (1.25 mg/kg LY3022859 ) for Participants Receiving a Weight-Based Dose
The MTD was defined as the highest dose level at which ≤33% of participants experienced a DLT during Cycle 1.
Time frame: First Dose through Cycle 1 (6 Weeks)
Population: All participants who received at least one dose of study drug and completed cycle 1 or discontinued treatment due to a DLT during the cycle 1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1.25 mg/kg LY3022859 | Maximum Tolerated Dose (MTD) of IMC-TR1 (1.25 mg/kg LY3022859 ) for Participants Receiving a Weight-Based Dose | NA milligram/kilogram (mg/kg) |
Secondary
Number of Dose-Limiting Toxicities (DLTs)
Time frame: First Dose through Cycle 1 (6 Weeks)
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1.25 mg/kg LY3022859 | Number of Dose-Limiting Toxicities (DLTs) | 2 DLTs |
| 12.5 mg LY3022859 | Number of Dose-Limiting Toxicities (DLTs) | 0 DLTs |
| 25 mg LY3022859 | Number of Dose-Limiting Toxicities (DLTs) | 2 DLTs |
Secondary
Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR) (Overall Response Rate [ORR]) (Antitumor Activity of IMC-TR1 as Monotherapy, Assessed Via Tumor Measurement by Response Evaluation Criteria in Solid Tumors, Version 1.1)
ORR is the best response of CR or PR as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST v1.1). CR is a disappearance of all target and non-target lesions and normalization of tumor marker level. PR is an at least 30% decrease in the sum of the diameters of target lesions (taking as reference the baseline sum diameter) without progression of not-target lesions or appearance of new lesions. Overall response rate is calculated as a total number of participants with CR or PR divided by the total number of participants with at least 1 measurable lesion, multiplied by 100.
Time frame: First Dose to Measured Progressive Disease (Up To 21.3 Weeks)
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1.25 mg/kg LY3022859 | Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR) (Overall Response Rate [ORR]) (Antitumor Activity of IMC-TR1 as Monotherapy, Assessed Via Tumor Measurement by Response Evaluation Criteria in Solid Tumors, Version 1.1) | 0 percentage of participants |
| 12.5 mg LY3022859 | Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR) (Overall Response Rate [ORR]) (Antitumor Activity of IMC-TR1 as Monotherapy, Assessed Via Tumor Measurement by Response Evaluation Criteria in Solid Tumors, Version 1.1) | 0 percentage of participants |
| 25 mg LY3022859 | Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR) (Overall Response Rate [ORR]) (Antitumor Activity of IMC-TR1 as Monotherapy, Assessed Via Tumor Measurement by Response Evaluation Criteria in Solid Tumors, Version 1.1) | 0 percentage of participants |
Secondary
Pharmacokinetics - Maximum Concentration (Cmax) of IMC-TR1
Time frame: Cycle (C) 1 Day (D) 1: 1, 2, 4, 8 hours (h); C1 D2: 24 h; C1 D3: 48 h; C1 D5: 96 h; C1 D8: 168 h; C1 D15: 336 h; C2 D15: 1, 2, 4, 8 h; C2 D16: 24 h; C2 D17: 48 h; C2 D19: 96 h; C2 D22: 168 h, C2 D29: 336 h
Population: All participants who received at least one dose of study drug and had evaluable PK data. PK of LY3022859 was not characterized at the 1.25 mg/kg dose level because of infusion interruptions thus no data collected.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 1.25 mg/kg LY3022859 | Pharmacokinetics - Maximum Concentration (Cmax) of IMC-TR1 | Cycle 1 | 4.34 microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 9 |
| 1.25 mg/kg LY3022859 | Pharmacokinetics - Maximum Concentration (Cmax) of IMC-TR1 | Cycle 2 | 3.52 microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 9 |
| 12.5 mg LY3022859 | Pharmacokinetics - Maximum Concentration (Cmax) of IMC-TR1 | Cycle 1 | 5.10 microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 21 |
| 12.5 mg LY3022859 | Pharmacokinetics - Maximum Concentration (Cmax) of IMC-TR1 | Cycle 2 | 5.01 microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 28 |
Secondary
Pharmacokinetics - Minimum Concentration (Cmin) of IMC-TR1
Pharmacokinetics - Minimum concentration (Cmin) of IMC-TR1
Time frame: Cycle 2 Day 1: Prior to fourth infusion 0 hour (h)
Population: All participants who received at least one dose of study drug and had evaluable PK data. PK of LY3022859 was not characterized at the 1.25 mg/kg dose level because of infusion interruptions thus no data collected.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| 1.25 mg/kg LY3022859 | Pharmacokinetics - Minimum Concentration (Cmin) of IMC-TR1 | NA microgram/milliliter (µg/mL) |
| 12.5 mg LY3022859 | Pharmacokinetics - Minimum Concentration (Cmin) of IMC-TR1 | NA microgram/milliliter (µg/mL) |
Secondary
Pharmacokinetics (PK) - Area Under the Concentration-time Curve (AUC[0-tlast]) and AUCτ of IMC-TR1
AUC (0-tlast) is area under the concentration versus time curve from the time zero to tlast. AUCτ is area under the concentration versus time curve during 1 dose interval (336 hours).
Time frame: Cycle (C) 1 Day (D) 1: 1, 2, 4, 8 hours (h); C1 D2: 24 h; C1 D3: 48 h; C1 D5: 96 h; C1 D8: 168 h; C1 D15: 336 h; C2 D15: 1, 2, 4, 8 h; C2 D16: 24 h; C2 D17: 48 h; C2 D19: 96 h; C2 D22: 168 h, C2 D29: 336 h
Population: All participants who received at least one dose of study drug and had evaluable PK data. PK of LY3022859 was not characterized at the 1.25-mg/kg dose level because of infusion interruptions thus no data collected.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 1.25 mg/kg LY3022859 | Pharmacokinetics (PK) - Area Under the Concentration-time Curve (AUC[0-tlast]) and AUCτ of IMC-TR1 | Cycle 1 (AUC[0-tlast]) | 28.5 microgram*hour per milliliter(µg·hr/mL) | Geometric Coefficient of Variation 18 |
| 12.5 mg LY3022859 | Pharmacokinetics (PK) - Area Under the Concentration-time Curve (AUC[0-tlast]) and AUCτ of IMC-TR1 | Cycle 1 (AUC[0-tlast]) | 60.2 microgram*hour per milliliter(µg·hr/mL) | Geometric Coefficient of Variation 30 |
| 12.5 mg LY3022859 | Pharmacokinetics (PK) - Area Under the Concentration-time Curve (AUC[0-tlast]) and AUCτ of IMC-TR1 | Cycle 2 (AUCτ) | 60.7 microgram*hour per milliliter(µg·hr/mL) | Geometric Coefficient of Variation 35 |