A Phase I/II Study of OPN-305 in Second-line Lower Risk Myelodysplastic Syndrome

Phase 1

Completed

Conditions: Myelodysplastic Syndrome

Interventions: Drug: OPN-305

Registration Number: NCT02363491

Lead Sponsor: Opsona Therapeutics Ltd.

Brief Summary: The dose-confirming part of this study, comprising at least 10 patients is designed as a single center, prospective, single arm, open label in patients who have failed or are unresponsive to Azacitidine (AZA) or Decitabine (they may also have additionally failed an Erythropoiesis Stimulating Agent (ESA) followed by a dose expansion part with at least 44 patients; the objective of the whole study being to assess the safety, efficacy, pharmacokinetics and pharmacodynamics of intravenously infused multiple doses of OPN-305 in low and intermediate-1 risk myelodysplastic syndrome (second and third line Lower risk MDS).

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 96

Inclusion Criteria

Written informed consent
Age ≥ 18 years
Diagnosis of MDS (de novo or secondary) by bone marrow aspirate based on the World Health Organization (WHO) classification - Low and Intermediate-1 risk categories MDS using the IPSS (International Prognostic Scoring System)
AZA/decitabine (this applies to standard of care and investigational drugs) failure (Dose confirming and Dose expansion parts):
defined as discontinuation due to any of the following:
- Lack of response after at least 4 cycles
- Loss of response (patient must have received therapy for at least 4 cycles)
- Progressive disease
- Adverse events

Note: Patients are eligible if additionally they have failed an ESA

HMA Naïve group:
- Never received a hypomethylating agent for MDS
- Failed or ceased to respond to ESA(s)
- ESA ineligible; defined as endogenous serum erythropoietin level > 200 U/L for subjects not previously treated with ESAs
Red blood cell transfusion dependent defined as ≥ 2 Red blood cells (RBC) units required in the 8 weeks prior to starting in the study. In addition, there should be no 8 consecutive weeks without red blood cell transfusions in the 16 weeks prior to enrolment.
Life expectancy ≥ 3 months
Eastern Cooperative Oncology Group (ECOG) performance status Grade 0-2
Serum bilirubin levels ≤2 x upper limits of normal (ULN)
Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels ≤2.5 x ULN
Del 5q patients who have failed or are not eligible for Revlimid
Creatinine clearance >30 ml/min calculated by the Cockcroft-Gault formula
Willingness to comply with the protocol procedures for the duration of the study, including scheduled follow-up visits and examinations
Negative urine β-human chorionic gonadotropin (β-HCG) pregnancy test for fertile women at screening and confirmed by serum pregnancy test in the 48 hours prior to OPN-305 administration
If sexually active female, patient must be/have one of the following:
Post-menopausal defined as the absence of menses for at least one year (serum Follicle-stimulating hormone (FSH) ≥20IU/L can also be measured according to local practice),OR
Surgically sterile defined as a bilateral tubal ligation at least 6 months prior to administration of study drug, bilateral oophorectomy, or complete hysterectomy, OR
Using an effective means of contraception that is planned to continue for the duration of treatment and for a further 3 months.
If sexually active male, patient must: Agree to use an effective means of contraception (per site-specific guidelines) that is planned to continue until 6 months after the last dose of OPN-305.Agree not to donate sperm until 6 months after the last dose of OPN-305

Exclusion Criteria

Diagnosis of MDS by bone marrow aspirate of Intermediate-2 and High risk category MDS based on the World Health Organization (WHO) classification using the IPSS (International Prognostic Scoring System)
Patients with 5q deletion (del) MDS eligible for Revlimid (lenalidomide)
Hypomethylating agent (HMA) Naïve group:
- Have received a hypomethylating agent for MDS
- Have not failed or ceased to respond to an ESA
- Are not ESA ineligible as defined in inclusion criteria
Prior history of acute leukemia or AML
Unable/unwilling to undergo bone marrow sampling
Prior history of bone marrow transplantation
Prior malignancy (other than non-invasive malignancy including in situ cervical cancer, Bowen's disease, basal cell cancer of the skin and non-invasive or excised skin squamous cell carcinoma) unless treated with curative intent and without evidence of disease for 3 years before randomization
Active viral or bacterial infections: this includes any infections that are being actively treated even if the signs and symptoms appear to have resolved. Courses of antibiotics or anti-viral treatment should be completed before the patients is enrolled
Unstable angina, congestive heart failure [NYHA (New York Heart Association) >class II], uncontrolled hypertension [diastolic > 100 mmHg], uncontrolled cardiac arrhythmia, or recent (within 1 year) myocardial infarction, uncontrolled diabetes mellitus
Clinical Evidence of Central Nervous System (CNS) disease
Less than 4 weeks since any therapy for MDS
Prior history of anaphylaxis to similar products
History or presence of a medical condition or disease or substance abuse that in the investigator's assessment would place the patient at an unacceptable risk for study participation
Lactating or pregnant woman

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
OPN-305	OPN-305	OPN-305

Primary Outcome Measures

Name	Time	Method
Establishment of the dose and dose frequency based on dose-limiting toxicity and bone marrow receptor occupancy of OPN-305 in low and intermediate -1 (Lower) risk MDS	8 weeks
Tolerability of OPN-305 as monotherapy based on adverse events	16 weeks/32 weeks (if there is no AZA add-back)
Tolerability of OPN-305 as monotherapy and in combination with AZA based on adverse events	32 weeks

Secondary Outcome Measures

Name	Time	Method
Pharmacokinetic profile of OPN-305 (maximum concentration (Cmax))	day 1, weeks 4, 8, 12, 16, 20, 24, 28, 32
Correlation of clinical response with cytogenical observations	wk 36
OPN-305 receptor occupancy in peripheral monocytes, bone marrow cells and stroma	screening (bone marrow only), day 1 (blood only), wks 4 (blood only), 8, 12 (blood only), 16, 20 (blood only), 24 (blood only), 28 (blood only), 32 and 36 (blood only)
Cytokine levels in serum (TNFα, IL-1β, IL-6, IL-10, IL-12, IL-18, IL-23 and IFN-γ)	day 1 and week 4
Pharmacokinetic profile of OPN-305 (time at which Cmax is attained (tmax))	day 1, weeks 4, 8, 12, 16, 20, 24, 28, 32
Hematological response based on International Working Group (IWG) 2000/2006	week 36
Immunogenicity of OPN-305 (Measurement of anti drug antibodies and neutralizing antibodies)	day 1, weeks 4, 8, 16, 24 and 32
Quality of life MD Anderson Symptom Inventory (MDASI) - Acute Myeloid Leukemia (AML)/Myelodysplastic syndrome (MDS) questionnaire	wk 36	MDASI is MD Anderson symptom inventory. It has two scales 1. Severity of symptoms scale 0-10 with 0 being not present and 10 being as bad as you can imagine 2. How symptoms interfere with life scale 0-10 with 0 did not interfere and 10 interfere completely
Incidence of infections	36 weeks