tTF-NGR Phase I Study

In this phase I clinical trial cancer patients suffering from solid tumors or lymphomas, recurring after and/or refractory against standard treatment are treated intravenously (iv) with increasing doses of tTF-NGR(tTF= truncated tissue factor; NGR=Asn-Gly-Arg). The objectives of this trial are to evaluate the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT) of intravenously (iv) infused daily applications of tTF-NGR for 5 days every 3 weeks in patients with cancer, who had obtained all standard treatment known for their disease entity prior to entry on study. Further objectives are to determine the perfusion and vascular volume fraction of measurable tumor lesions versus normal reference tissue before and after tTF-NGR application by MRI as a biological surrogate parameter for biological activity of the investigational medicinal product (IMP), tTF-NGR, and to obtain pharmacokinetic data.

PHASE I STUDY OF tTF-NGR IN PATIENTS WITH RECURRENT OR REFRACTORY MALIGNANT TUMORS OR LYMPHOMAS BEYOND ALL STANDARD TREATMENTS

Short Title: tTF-NGR Phase I Study Sponsor's Study Code: UKM12_0018

EudraCT-No.: 2016-003042-85 Sponsor: Universitätsklinikum Muenster Investigator: Prof. Dr. Christoph Schliemann

Indication: All solid tumors and lymphomas beyond standard therapy Study Design: Phase I Study Investigational Medicinal Product: tTF-NGR

Therapy: Phase I, open label, single arm, non-randomized prospective, monocenter study. tTF-NGR will be given as 1-hour infusion via central venous access once daily for 5 days with a subsequent rest period of 2 weeks and following cycles with dose escalation of 0.5 mg/m2 upon judgement of tolerability and therapeutic activity. Starting dose will be 1 mg/m2/day. Patients within the dose-escalation part will be treated in sequence and not in parallel. Individual patients can undergo a maximum of 8 dose-escalations. Dose-escalation is stopped before the maximum number of 8 escalation steps if tumor response, tumor progression or a Dose-Limiting Toxicity (DLT) is observed. In the case of stable disease (SD) and with good tolerability these patients can obtain further cycles without dose-escalation until tumor progression or Dose-Limiting Toxicity (DLT) and the next patient can start with dose-escalation cycles on the highest tolerable dose for the previous patient.

Objectives:

Primary Objective:

To evaluate the maximum tolerated dose (MTD) and the Dose-Limiting Toxicity (DLT) of intravenously (iv) infused daily applications of tTF-NGR for 5 days every 3 weeks in patients with relapsed or refractory cancer, who had obtained all standard treatment known for their disease entity prior to entry on study.

Secondary Objectives:

1. To determine the perfusion and vascular volume fraction of measurable tumor lesions versus normal reference tissue before and after tTF-NGR application as a biological surrogate parameter for biological activity of the IMP in the patients treated within the verification cohorts.
2. To obtain pharmacokinetic data of tTF-NGR.

Endpoints:

Primary Safety Endpoint: Maximum Tolerated Dose (MTD). MTD is the dose below the dose leading to reproducible episodes of Dose Limiting Toxicity (DLT) in at least 2/6 patients. DLT will be characterized by clinical, blood and serum monitoring at specified time points before and during study period.

Secondary Efficacy Endpoints:

1. Occurrence and frequency of inhibition of tumor blood flow as measured by contrast-enhanced Magnetic Resonance Imaging (MRI) in the patients treated in the verification cohorts.
2. Occurrence and frequency of tumor response defined as Complete Response (CR), Partial Response (PR), or Stabile Disease (SD) as defined by RECIST criteria.

Inclusion Criteria:

* age \> 18 years
* histologically proven or cytologically confirmed solid malignant tumor or malignant lymphoma
* recurrent or refractory disease after standard therapy and with no known curative or survival-prolonging treatment options according to the judgement of the investigators
* life expectancy of at least 6 weeks according to the judgement of the investigators
* Karnofsky performance status \>50
* measurable disease with at least one marker-lesion measurable in 2 dimensions by Vascular Volume-Fraction-MRI
* adequate bone marrow function with absolute neutrophil count \> 1000/microliter and platelet count \> 50/nl.
* normal global coagulation parameters (Quick, PTT, TZ, fibrinogen), no prophylactic anticoagulation
* adequate liver function (total bilirubin \< 3x the upper normal limit (ULN), SGPT/SGOT \< 3x ULN)
* adequate renal function (serum creatinine \< 3x ULN)
* no history of coronary heart disease, stroke, transitory ischemic attacks, pulmonary embolism, or deep vein thrombosis
* time elapsed from previous therapy (including other IMPs) \> 3 weeks with recovery from side effects
* exclusion of central nervous system (CNS) disease and CNS vascular abnormalities by MRI
* ability to understand and provide written informed consent
* written informed consent given
* for female patients with child-bearing potential exclusion of pregnancy by adequate testing within 48 hours prior to entry on study
* females of childbearing potential as well as fertile males must agree to use a highly effective form of contraception (Pearl Index \< 1) during the study and for 120 days following the last dose of the IMP

Exclusion Criteria:

* clinically significant unrelated illness which in the judgement of the investigators could compromise the patient's ability to tolerate the IMP or be likely to interfere with the study procedures or results
* known hypersensitivity reactions to prior application of E. coli-derived material
* women with breast-feeding activity
* concomitant use of any other investigational agent (agent for which there is currently no approved indication from regulatory authorities)
* clinical application of any other drug with known antitumor activity
* prophylactic anticoagulation within the last 3 days

NOTE: Since this is a phase I study for end-stage cancer patients, patients who would be excluded from the protocol strictly for laboratory abnormalities only can be included at the Investigator's discretion. This will be documented as an exception to the criteria and will be signed and filed in the CRF and the Trial Master File.

Statistical Methods: Descriptive statistics are performed to characterize MTD (= dose level below DLT occurring in 2/6 patients) Financial Support: Deutsche Krebshilfe, grant 111004 Schedule Planned start date of the study (FPFV): 01.11.2016 Planned end date of recruitment (LPFV): 01.11.2017 Planned end date of the study (LPLV): 01.05.2018

Studied period (years): (date of first enrolment) 2017 03 29; (date of last completed) 2019 12 19

Study centre: Department of Medicine A (Hematology, Hemostaseology, Oncology) University Hospital Muenster, Germany Albert-Schweitzer-Campus 1 D-48149 Muenster, Germany

Methodology:

We have treated 17 patients with advanced cancer beyond standard therapies with tTF-NGR applied as a 1-hour infusion via central venous access for 5 consecutive days and rest periods of 2 weeks before the next cycle. The study allowed for intraindividual dose escalations from cycle to cycle and established MTD and DLT by verification cohorts of 6 patients. This was an investigator-initiated, monocenter, single-arm, open-label study.

Number of patients (planned and analysed):

The number of patients required to complete this study was determined by the occurrence of DLT. Eventually, 24 patients had to be screened and 17 of them treated and analyzed in order to evaluate the study.

Eligibility Criteria:
Inclusion criteria:

* age ≥ 18 years
* histologically proven or cytologically confirmed solid malignant tumor or malignant lymphoma
* recurrent or refractory disease after standard therapy and with no known curative or survival-prolonging treatment options according to the judgement of the investigators
* life expectancy of at least 6 weeks according to the judgement of the investigators
* Karnofsky performance status ≥ 50
* measurable disease with at least one marker-lesion measurable in 2 dimensions by Vascular Volume-Fraction-MRI and/or CEUS.
* adequate bone marrow function with absolute neutrophil count \> 1000/microliter and platelet count \> 50/nl
* normal global coagulation parameters (Quick, partial thromboplastin time (PTT), thrombin time (TZ), fibrinogen), no prophylactic anticoagulation
* ability to understand and provide written informed consent
* adequate liver function (total bilirubin \< 3x the upper normal limit (ULN), serum glutamic pyruvic transaminase/serum glutamic-oxaloacetic transaminase (SGPT/SGOT) \< 3x ULN)
* adequate renal function (serum creatinine \< 3x ULN)
* no history of coronary heart disease, stroke, transitory ischemic attacks, pulmonary embolism, or deep vein thrombosis
* time elapsed from previous therapy (including other IMPs) ≥ 3 weeks with recovery from side effects
* exclusion of central nervous system (CNS) disease and CNS vascular abnormalities by MRI
* ability to understand and provide written informed consent
* written informed consent given
* for female patients with child-bearing potential exclusion of pregnancy by adequate testing within 48 hours prior to entry on study
* females of childbearing potential as well as fertile males must agree to use a highly effective form of contraception (Pearl Index \< 1) during the study and for 120 days following the last dose of the IMP

Exclusion criteria:

* clinically significant unrelated illness which in the judgement of the investigators could compromise the patient's ability to tolerate the IMP or be likely to interfere with the study procedures or results
* known hypersensitivity reactions to prior application of E. coli-derived material
* women with breast-feeding activity
* concomitant use of any other investigational agent (agent for which there is currently no approved indication from regulatory authorities)
* clinical application of any other drug with known anti tumor activity
* prophylactic anticoagulation within the last 3 days

NOTE: Since this is a phase I study for end-stage cancer patients, patients who would be excluded from the protocol strictly for laboratory abnormalities only can be included at the Investigator's discretion. This will be documented as an exception to the criteria and will be signed and filed in the CRF and the Trial Master File.