A Study of IMC-TR1 in Participants With Advanced Solid Tumors

Phase 1

Completed

• Conditions: Neoplasms; Tumor
• Interventions: Biological: IMC-TR1

• Registration Number: NCT01646203
• Lead Sponsor: Eli Lilly and Company

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.

Study Timeline

• Study First Submitted: 2012-06-11
• Study Start: 2012-07
• Study First Submitted QC: 2012-07-18
• Study First Posted: 2012-07-20
• Primary Completion: 2014-10
• Study Completion: 2014-10
• Results First Submitted: 2017-09-27
• Status Verified: 2018-08
• Results First Submitted QC: 2018-08-03
• Last Update Submitted: 2018-08-03
• Results First Posted: 2019-01-18
• Last Update Posted: 2019-01-18

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 14

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
IMC-TR1	IMC-TR1	Part A - Dose Escalation: Cohort 1A: 1.25 mg/kg, intravenously (IV), every 2 weeks of the 6-week treatment cycle Cohorts 1B-9: Dose Escalation from 12.5 mg to 1600 mg (flat dose), intravenously (IV), every 2 weeks of the 6-week treatment cycles Cohorts 10-12: Dose escalation from 800 mg to 1600 mg (flat dose), intravenously (IV), weekly during the 6-week treatment cycles Part B - Disease Specific Cohort Expansion: Participants will be enrolled into each of three tumor-specific cohort expansions. Participants will be treated with recommended Phase 2 dose.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
Number of Dose-Limiting Toxicities (DLTs)	First Dose through Cycle 1 (6 Weeks)
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
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.
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
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.
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 - Minimum Concentration (Cmin) of IMC-TR1	Cycle 2 Day 1: Prior to fourth infusion 0 hour (h)	Pharmacokinetics - Minimum concentration (Cmin) of IMC-TR1

Trial Locations

Locations (1)

For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician; 🇺🇸 San Antonio, Texas, United States