Dose Escalation Study MORAb-066 Targeting Tissue Factor (TF)-Expressing Malignancies Including Breast, Pancreatic, Colorectal, NSCLC

A Phase I Study of the Safety, Tolerability, and Pharmacokinetics of MORAb-066, a Humanized Monoclonal Antibody to Human Tissue Factor, in Patients With Advanced or Metastatic Breast, Pancreatic, Colorectal, or Non-Small Cell Lung Cancer (Adenocarcinoma) Malignancies

This study is a Phase I, first in human, dose-escalation study of MORAb-066, an investigational humanized immunoglobulin G (IgG) monoclonal antibody (mAb) that targets TF-expressing malignancies that include breast, pancreatic, colorectal, and non-small-cell lung cancer (NSCLC) (adenocarcinoma). This open-label study will assess the safety, tolerability, and pharmacokinetics of MORAb-066 administered weekly. This study will identify the maximum tolerated dose (MTD) when MORAb-066 is administered IV once weekly on a 28-day cycle.

Study Overview

• Status: Completed
• Conditions: Adenocarcinoma; Breast Cancer; Carcinoma, Non-Small-Cell Lung; Colorectal Cancer; Pancreatic Cancer
• Intervention / Treatment: Drug: MORAb-066

Detailed Description

Primary Objective

-To evaluate the safety and tolerability of weekly intravenous (IV) infusions of MORAb-066.

Secondary Objectives

• To identify the dose-limiting toxicities (DLT) and to determine the maximum tolerated dose (MTD) of MORAb-066.
• To characterize the pharmacokinetic (PK) properties of MORAb-066.
• To identify, on the basis of safety, PK, and pharmacodynamics (PDx) data, a recommended Phase II dose and schedule for MORAb-066.
• To make a preliminary assessment of the antitumor activity of MORAb-066.
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• To detect any antibody response (i.e., human antihuman antibodies [HAHA]) to multiple IV infusions to MORAb-066.

Exploratory Objectives

• To evaluate the presence of tissue factor (TF) substrates such as protease activated receptor 2 when applicable.
• To evaluate the archived tumor tissue for TF overexpression by immunohistochemistry.
• To evaluate whether there are potential biomarkers that correlate responses to MORAb-066.

• Study Type: Interventional
• Enrollment (Actual): 27
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Oklahoma
    • Oklahoma City, Oklahoma, United States
  • Tennessee
    • Nashville, Tennessee, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Patients must meet the following criteria in order to be included in this clinical trial:

1. Histologically or cytologically confirmed diagnosis of breast, colorectal, pancreas, or NSCLC (adenocarcinoma) that is metastatic or unresectable for which there is no effective therapy.
2. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1 (see Appendix A).
3. Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
4. Subject has recovered (to Grade less than or equal to 1) from all clinically significant toxicities related to prior antineoplastic therapies with the exception of alopecia and bone marrow and organ functions (described separately below).

5. Adequate organ system function less than or equal to 2 weeks prior to Day1, defined as follows:

   • Absolute neutrophil count (ANC) greater than or equal to 1.5 x 10^9/L
   • Platelets greater than or equal to 100 x 10^9/L
   • Hemoglobin greater than or equal to 9 g/dL
   • Prothrombin time/partial thromboplastin time (PT/PTT) within institutional limits of normal
   • Serum total bilirubin less than or equal to 1.5 times the upper limit of normal (ULN)
   • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to 3.0 x ULN if no liver involvement or less than or equal to 5 x ULN with liver involvement.
   • Serum creatinine less than or equal to 1.5 x ULN or calculated creatinine clearance greater than or equal to 50 mL/min as calculated by the Cockcroft-Gault method, OR 24-hour measured urine creatinine clearance greater than or equal to 50 mL/min.
6. Life expectancy of greater than or equal to 12 weeks.
7. Female patients of child-bearing potential (see Appendix C), and all male patients must consent to use a medically acceptable method of contraception throughout the study period and for 30 days after their last MORAb-066 administration. A barrier method of contraception must be included.
8. Patients must be greater than or equal to 18 years of age.
9. Patients entering this study will be asked to provide archival tissue from a previous tumor biopsy (if available) for correlative testing. If tissue is not available, the subject will still be eligible for enrollment into the study.
10. Ability to understand the nature of this study and give written informed consent.

Exclusion Criteria:

Patients who meet any of the following criteria will be excluded from trial entry:

1. Patients currently receiving cancer therapy (i.e., chemotherapy, radiation therapy, immunotherapy, biologic therapy, hormonal therapy, surgery and/or tumor embolization).
2. Use of an investigational drug within 21 days or 5 half-lives (whichever is shorter) prior to the first dose of MORAb-066. For investigational drugs for which 5 half-lives is less than 21 days, a minimum of 10 days between termination of the investigational drug and administration of MORAb-066 is required.
3. Any major surgery, chemotherapy, radiotherapy, or immunotherapy within the last 21 days (limited palliative radiation is allowed greater than or equal to 2 weeks).
4. Subject has received wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) less than or equal to 28 days or limited field radiation for palliation less than or equal to 14 days prior to starting study drug or has not recovered from side effects of such therapy.
5. Known intracranial involvement, leptomeningeal metastases or spinal cord compression due to disease.
6. Known allergy or hypersensitivity to monoclonal antibodies.
7. Known bleeding diathesis, such as factor deficiency, factor inhibitor, platelet disorder, or who are on active anticoagulation, or any dose of aspirin within 5 days prior to first dose of MORAb-066.
8. Known prior significant bleeding history.
9. Patients with ureteral stents or 3+ blood in the urine at baseline.
10. Patients who are receiving chronic systemic anticoagulation therapy (warfarin sodium or heparin, etc.).
11. Patients who received a previous mAb therapy and have evidence of an immune or allergic reaction or previously documented HAHA reaction.
12. A serious non-healing wound, active ulcer, or untreated bone fracture. An abdominal fistula or gastrointestinal perforation less than 6 months prior to treatment.
13. History of hematemesis or hemoptysis (defined as having bright red blood of 1/2 teaspoon or more per episode) less than or equal to 1 month prior to study enrollment.

14. Subject has cardiac dysfunction including any of the following:

    • Myocardial infarction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of left ventricular ejection fraction function
    • QTcF greater than 470 msec
    • History of documented congestive heart failure (New York Heart Association functional classification III-IV [see Appendix B])
    • Angina not well-controlled by medication
15. A serious active infection (bacterial or fungal) at the time of treatment, or another serious underlying medical condition that would impair the ability of the subject to receive protocol treatment.
16. Chronic inflammatory disorder(e.g., inflammatory bowel disease, active vasculitis).
17. Herbal preparations/medications must be discontinued 7 days prior to first dose of study drug (see Section 5.3.1).
18. Known diagnosis of human immunodeficiency virus, Hepatitis B or Hepatitis C.
19. History or current diagnosis of glomerulonephritis
20. History of clinically significant or current diagnosis of hematuria.
21. Women who are pregnant or lactating.
22. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.
23. Concurrent condition that in the investigator's opinion would jeopardize compliance with the protocol.
24. Inability or unwillingness to comply with study and/or follow-up procedures outlined in the protocol.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MORAb-066 0.1 mg/kg; Participants will receive MORAb-066 0.1 milligram per kilogram (mg/kg), infusion intravenously, on Days 1, 8, 15, and 22, in each 28-day treatment cycle until disease progression, participant's discontinuation due to unacceptable toxicity, withdrawal by participants, or discontinuation by study physician decision.	Drug: MORAb-066; MORAb-066 infusion.
Experimental: MORAb-066 0.3 mg/kg; Participants will receive MORAb-066 0.3 mg/kg, infusion intravenously, on Days 1, 8, 15, and 22, in each 28-day treatment cycle until disease progression, the participant discontinuation due to unacceptable toxicity, withdrawal by participants, or discontinuation by study physician decision.	Drug: MORAb-066; MORAb-066 infusion.
Experimental: MORAb-066 1 mg/kg; Participants will receive MORAb-066 1 mg/kg, infusion intravenously, on Days 1, 8, 15, and 22, in each 28-day treatment cycle until disease progression, the participant's discontinuation due to unacceptable toxicity, withdrawal by participants, or discontinuation by study physician decision.	Drug: MORAb-066; MORAb-066 infusion.
Experimental: MORAb-066 2 mg/kg; Participants will receive MORAb-066 2 mg/kg, infusion intravenously, on Days 1, 8, 15, and 22, in each 28-day treatment cycle until disease progression, the participant's discontinuation due to unacceptable toxicity, withdrawal by participants, or discontinuation by study physician decision.	Drug: MORAb-066; MORAb-066 infusion.
Experimental: MORAb-066 3 mg/kg; Participants will receive MORAb-066 3 mg/kg, infusion intravenously, on Days 1, 8, 15, and 22, in each 28-day treatment cycle until disease progression, the participant discontinuation due to unacceptable toxicity, withdrawal by participants, or discontinuation by study physician decision.	Drug: MORAb-066; MORAb-066 infusion.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	Safety assessments consisted of monitoring and recording all AEs and SAEs; regular monitoring of hematology, blood chemistry, urine values, and vital signs; periodic measurement of electrocardiograms (ECGs) and Eastern Cooperative Oncology Group (ECOG) assessments; and performance of physical examinations.	First dose of study drug (Baseline) up to 30 days after last dose of study drug (Up to approximately 2 years 7 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Dose Limiting Toxicity (DLT)	DLT was defined using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 as any grade 3 or 4 hematemesis, hemoptysis, hematochezia, bright red blood per rectum, epistaxis, gingival bleeding, hemarthrosis, haematuria, uncontrollable menses, or any other bleeding thought to be significant as per assessment of the investigator, regardless of grade.	Cycle 1 (Cycle length=28 days)
Maximum Tolerated Dose (MTD)	The MTD was defined as the highest dose level at which no more than one out of six participants experienced DLT. DLT was defined using NCI CTCAE Version 4.03 as any grade 3 or 4 hematemesis, hemoptysis, hematochezia, bright red blood per rectum, epistaxis, gingival bleeding, hemarthrosis, haematuria, uncontrollable menses, or any other bleeding thought to be significant as per assessment of the investigator, regardless of grade.	Cycle 1 (Cycle length=28 days)
Cmax: Maximum Observed Serum Concentration for MORAb-066		Cycle 1 Days 1 and 22: 0-168 hours post-dose (Cycle length=28 days)
Tmax: Time to Reach Maximum Serum Concentration for MORAb-066		Cycle 1 Days 1 and 22: 0-168 hours post-dose (Cycle length=28 days)
t1/2: Terminal Elimination Phase Half-Life for MORAb-066		Cycle 1 Days 1 and 22: 0-168 hours post-dose (Cycle length=28 days)
AUC(0-t): Area Under the Serum Concentration-time Curve From Zero Time to the Last Measurable Point for MORAb-066		Cycle 1 Days 1 and 22: 0-168 hours post-dose (Cycle length=28 days)
AUC(0-Inf): Area Under the Serum Concentration-time Curve From Zero to Infinity for MORAb-066		Cycle 1 Days 1 and 22: 0-168 hours post-dose (Cycle length=28 days)
Vd: Volume of Distribution for MORAb-066		Cycle 1 Days 1 and 22: 0-168 hours post-dose (Cycle length=28 days)
CL: Total Body Clearance for MORAb-066		Cycle 1 Days 1 and 22: 0-168 hours post-dose (Cycle length=28 days)
Number of Participants With Best Overall Response (BOR)	BOR based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for target and non-target lesions is complete response (CR) or partial response (PR). CR: disappearance of target and non-target lesions, normalization of tumor marker level, all lymph nodes must be non-pathological in size (less than 10 millimeter [mm] short axis). PR: at least 30 percent (%) decrease in sum of diameters (SOD) of target lesions, taking as reference the baseline SOD persistence of one or more non-target lesions and/or maintenance of tumor marker level above the normal limits. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest SOD. PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.	Up to approximately 2 years 7 months
Number of Participants Positive for Antidrug Antibodies (ADA)		Up to approximately 2 years 7 months

Collaborators and Investigators

• Sponsor: Morphotek
• Collaborators: SCRI Development Innovations, LLC
• Investigators: Principal Investigator: Kathleen Moore, MD, Oklahoma University

Study record dates

Study Major Dates

• Study Start (Actual): June 19, 2013
• Primary Completion (Actual): February 9, 2016
• Study Completion (Actual): February 9, 2016

Study Registration Dates

• First Submitted: January 3, 2013
• First Submitted That Met QC Criteria: January 3, 2013
• First Posted (Estimated): January 4, 2013

Study Record Updates

• Last Update Posted (Actual): March 29, 2024
• Last Update Submitted That Met QC Criteria: September 26, 2023
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms by Histologic Type; Neoplasms; Lung Diseases; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Adenocarcinoma
• Other Study ID Numbers: MORAb-066-001