Safety and Pharmacokinetics of Rising Doses of APO010 in Relapsed/Refractory Multiple Myeloma Patients Selected by DRP (SMR-3184)

Allarity Therapeutics

Status and phase

Terminated

Phase 2

Phase 1

Conditions

Relapsed/Refractory Multiple Myeloma

Treatments

Drug: APO010

Study type

Interventional

Funder types

Other

Industry

Identifiers

NCT03196947

APO010/P1/002

Details and patient eligibility

About

Multicentre, open label, uncontrolled, phase I pharmacokinetic study, to determine the Maximum Tolerated Dose (MTD) of APO010 administered intravenously on D1, D8 and D15 followed by a one-week drug rest, in patients with multiple myeloma for who have relapsed or are refractory to 2 (in high-risk patients 1) or more different prior therapies and who have Drug Response Predictor (DRP) for APO010 indicating a higher likelihood for response to APO010. The study will contain an extension phase where the recommended Dose will be tested on additional patients.

Full description

APO010 is a novel investigational antitumour agent. It is a recombinant form of human Fas ligand (FasL), a protein with the function of inducing programmed cell death (apoptosis). Preclinical studies indicate that multiple myeloma is sensitive for APO010. Estimation of DRP for APO010 in myeloma patients suggests that it may be possible to identify patients with high and low likelihood for response, and thereby allocate the predicted high likelihood patients to the treatment. Preclinical results indicate that, in comparison with other single agents, APO010 exercises superior anti-tumour effect by inducing apoptosis.

The study will include patients with multiple myeloma who have relapsed or are refractory to 2 (in high-risk patients 1) or more different prior therapies, including IMiDs and PI and who have Drug Response Predictor (DRP) for APO010 indicating a higher likelihood for response to APO010.

This study is a multicentre, open label, uncontrolled, phase I, dose escalation, pharmacokinetic study, to determine the Maximum Tolerated Dose (MTD) of APO010 administered intravenously on D1, D8 and D15 followed by a one-week drug rest i.e. cycle duration is 4 weeks. The study will contain an extension phase where the Recommended Dose will be tested on additional patients.

The primary endpoint is determination of the Maximum Tolerated Dose (MTD)based upon first cycle drug-related dose-limiting toxicity and the recommended dose of APO010. Safety will be evaluated during the study and for 30 days after the last administration of study drug. Adverse events and laboratory studies will be graded according to NCI-CTCAE v. 4.03.

The proportion of patients with positive HADA assessment will be investigated and a description of any objective tumour response based on International Myeloma Working Group criteria and from changes in M-protein and iFLC.

Enrollment

1 patient

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Relapsed or relapsed/refractory to 2 (in high-risk patients 1) or more different prior therapies, including IMiDs and PI
Measurable disease
Serum M-protein > 10 g/l, or
Urine M-protein > 200 mg/24 hours, or
Serum involved-FLC (iFLC) > 100 mg/l and abnormal FLC ratio
Have participated in the APO010 screening protocol in which Drug Response Predictor (DRP) outcome is measured as being in the upper likelihood of response (50% in dose-finding part and 25% in the expansion cohort)
Age > 18 years
Adequate organ and bone marrow function as defined below:
Absolute neutrophil count > 1.5 x 109/l (> 0.75 x 109/l in case > 50% plasma cell count in bone marrow)
Platelet count > 50 x 109/l (> 30 x 109/l in case > 50% plasma cell count in bone marrow)
Haemoglobin > 4.6 mmol/l (> 7.5 g/l)
Bilirubin ≤ upper limit of normal
aspartate aminotransferase (SGOT)/alanine transaminase (SGPT) ≤ upper limit of normal
Creatinine < 1.5 x upper limit of normal or creatinine clearance > 50 ml/min calculated according to Cockcroft-Gault
Eastern Cooperative Oncology Group (ECOG) performance status < 2
Life expectancy of at least 3 months.
Capability of understanding the nature of the study and giving written informed consent
Signed informed consent form

Exclusion criteria

Have central nervous system (CNS) myeloma
Have plasma cell leukaemia defined as plasma cell count > 2000 / µL in peripheral blood
Have symptomatic amyloidosis
Have anti-myeloma treatment or radiotherapy within 3 weeks from first infusion
Have received a cumulative dose of corticosteroid > 200 mg (dexamethasone, or equivalent dose of prednisone) within 2 weeks of the first infusion
Have received any experimental drug or experimental therapy within 3 weeks before the first infusion
Have received autologous-stem cell transplantation (SCT) within 12 weeks before the first infusion
Have received an allogeneic stem cell transplantation (SCT)
Have had past or current malignancy except for:
Cervical carcinoma < Stage 1B
Non-invasive basal cell or squamous cell skin carcinoma
Malignant melanoma with CR of > 10 years
Any other curable cancer with a CR > 5 years
Have major surgery within 4 weeks prior to the first infusion
Have severe infection requiring iv treatment
Have known HIV positivity
Have known active hepatitis B or C
Have had clinical significant arteriosclerotic events:
Ischemic heart disease
Unstable angina
Myocardial infarction
Transient ischemic attack
Ischemic stroke
Documented peripheral arteriosclerosis
Have baseline QT interval as corrected by Fridericia's formula (QTcF) > 470 msec for female patients or > 450 msec for male patients or a complete left bundle branch block (defined as QRS interval > 120 msec in left bundle branch block form)
CNS disease including epilepsy or altered mental status precluding understanding of the informed consent process and/or completion of the necessary study procedures
Women of childbearing age and potential who are not willing to use effective contraception during the study and at least until 90 days after last dose of study drug. Male patients or male patients who have female partners of childbearing age and potential who are not willing to use effective contraception during the study and at least until 90 days after last dose of study drug. Highly effective methods of birth control are defined as those which result in a low failure rate, i.e., less than 1% per year, when used consistently and correctly such as implants, injectables, combined oral contraceptives, some intra-uterine devices, sexual abstinence or vasectomized partner
Pregnant or breast-feeding women