SOAR: Eltrombopag Combined With Cyclosporine as First Line Therapy in Patients With Severe Acquired Aplastic Anemia

Sponsor
Novartis Pharmaceuticals (Industry)
Overall Status
Completed
CT.gov ID
NCT02998645
Collaborator
(none)
54
20
1
59.7
2.7
0

Study Details

Study Description

Brief Summary

This interventional Phase II, single-arm, multicenter, open-label study will investigate the efficacy and safety of a combination regimen of 6 months eltrombopag and cyclosporine treatment in adult patients with severe aplastic anemia (SAA) as first line therapy, with an additional 18 months follow-up for cyclosporine tapering and duration of response until relapse or 24 months whichever is earlier (responders only who do not relapse prior to 6 months).

The usage of eltrombopag and cyclosporine combines two therapies with different modes of action. Cyclosporine acts as an immunosuppressant and eltrombopag acts as a stimulator of bone marrow progenitor cells. Given that SAA is currently viewed as having an autoimmune pathogenesis resulting in bone marrow progenitor cell destruction, the combination of eltrombopag and cyclosporine is attractive. Preliminary experience with their combined use appears favorable, with no untoward toxicity observed to date.

Condition or Disease Intervention/Treatment Phase
Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
54 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
SOAR, Interventional Phase II Single-arm Study to Assess Efficacy and Safety of Eltrombopag Combined With Cyclosporine as First Line Therapy in Adult Patients With Severe Acquired Aplastic Anemia
Actual Study Start Date :
May 11, 2017
Actual Primary Completion Date :
Nov 3, 2020
Actual Study Completion Date :
May 2, 2022

Arms and Interventions

Arm Intervention/Treatment
Experimental: Eltrombopag + cyclosporine

Planned duration of treatment with eltrombopag & cyclosporine is 6 months (for all patients); the planned duration of treatment with cyclosporine (cyclosporine tapering) is 18 months (for responder patients only).

Drug: eltrombopag
Film-coated tablets (12.5 mg, 25 mg, 50 mg and 75 mg) administered orally, once daily. Dosing is done according to age and ethnicity (East Asian)

Drug: Cyclosporine
Supplied in oral soft gel capsules or oral solution and dosage is based on body weight and administered every 12 hours. Dosing is titrated individually according to therapeutic trough level for 6 months. After 6 months (for responders), tapering of cyclosporine must be done as follows: 6-9 months: at the 6 months visit, the dose must be reduced by 25% for 3 months 9-12 months: at the 9 months visit, the dose must be further reduced by 25% for another 3 months 12-24 months: maintain dose

Outcome Measures

Primary Outcome Measures

  1. Overall hematologic response (CR + PR) rate - 6 month [by 6 months]

    Overall hematologic response = patients with complete response (CR) + patients with partial response (PR). Partial response is defined as any two of the following parameters at two consecutive measurements at least 7 days apart during the study: Absolute neutrophil count (ANC) >500/μL Platelet count >20 000/μL Reticulocyte count >60 000/μL Complete response is defined as all three parameters meet the following criteria at two consecutive measurements at least 7 days apart during the study: Absolute neutrophil count (ANC) > 1 000/μL Platelet count >100 000/μL Hemoglobin >10 g/L

Secondary Outcome Measures

  1. Overall hematologic response (CR + PR) rate - 3, 12 and 24 month [by 3 months (all patients) and at 12 and 24 months (responders only)]

    Overall hematologic response = patients with complete response (CR) + patients with partial response (PR). Partial response is defined as any two of the following parameters at two consecutive measurements at least 7 days apart during the study: Absolute neutrophil count (ANC) >500/μL Platelet count >20 000/μL Reticulocyte count >60 000/μL Complete response is defined as all three parameters meet the following criteria at two consecutive measurements at least 7 days apart during the study: Absolute neutrophil count (ANC) > 1 000/μL Platelet count >100 000/μL Hemoglobin >10 g/L

  2. Duration of hematologic response [by 6 months (all patients) and 24 months (responders only)]

    Time from the date of the start of first response to the date of first relapse (defined as no longer meeting definition of PR (and not CR)

  3. Proportion of patients who relapse [by 6 months (all patients) and 24 months (responders only)]

    Percentage of patients who relapse. Relapse is defined as no longer meeting the definition of PR (and not CR).

  4. Percentage of patients with clonal evolution to myelodysplasia, paroxysmal nocturnal hemoglobinuria (PNH), and leukemia [by 6 months (all patients) and 24 months (responders only)]

    Clonal evolution to myelodysplasia is defined as a new marrow cytogenic abnormality with or without characteristic dysplastic marrow findings. Evolution to leukemia is defined as greater than 20% peripheral blood and/or marrow blasts. Evolution to paroxysmal nocturnal hemoglobinuria (PNH) is defined as a clone at baseline < 10% that rose to greater than 50% on study.

  5. Percentage of patients who are red blood cells (RBC) transfusion independent [by 6 months (all patients) and 24 months (responders only)]

    Percentage of patients who are RBC transfusion independent at least once by 6 months and by 24 months. Independence defined as no RBC transfusion for at least 56 days.

  6. Percentage of patients who are platelet transfusion independence [by 6 months (all patients) and 24 months (responders only)]

    Percentage of patients who are platelet transfusion independent at least once by 6 months and by 24 months. Independence defined as no platelet transfusion for at least 28 days.

  7. Longest interval without platelet or RBC transfusion [by 6 months (all patients) and 24 months (responders only)]

    Duration of longest interval without a platelet or RBC transfusion by 6 months and by 24 months.

  8. Change from baseline in scores of FACIT-Fatigue Patient Reported Outcome [Baseline and by 6 months (all patients) and 24 months (responders only)]

    FACIT-Fatigue responses will be generated in accordance with the respective scoring manual. Patients with an evaluable baseline score and at least one evaluable post baseline score during the treatment period will be included in the change from baseline analyses. The FACT- Fatigue is a 13-item fatigue subscale that asks the patient to rate their degree of tiredness, weakness and fatigue. All items of the FACT-Fatigue use a 5 point scale ranging from 0 to 4 with a 0 rating being "not at all" and a 4 rating being "very much". Total score ranges from 0 to 52. High scores represent less fatigue.

  9. Change from baseline in scores of FACT-TH18 Patient Reported Outcome [Baseline and by 6 months (all patients) and 24 months (responders only)]

    FACT-TH18 responses will be generated in accordance with the respective scoring manual. Patients with an evaluable baseline score and at least one evaluable post baseline score during the treatment period will be included in the change from baseline analyses. FACT-TH18 is comprised of FACT-G and a thrombocytopenia specific questionnaire. FACT-G consists of 27-items divided into 4 QOL domains (physical well-being, social/Family well-being, emotional and functional well-being). FACT-TH18 has 18-items which asks the patient to rate degree of thrombocytopenia. All items of the FACT-TH18 use a 5 point scale ranging from 0 to 4 with a 0 rating being "not at all" and a 4 rating being "very much".

  10. Frequency and severity of AEs and serious AEs (SAEs) [by 6 months (all patients) and 24 months (responders only)]

    Safety will be assessed by frequency and severity of AEs, serious AEs (SAEs) based on the CTCAE version 4. 03, and AEs leading to discontinuation, and evaluating changes in laboratory values within 6 months and within 24 months (responders only)

  11. Pharmacokinetic parameter- Cmax of eltrombopag when combined with cyclosporine [Week 2:hour 0,2,4,6,8 Week 4,8,12,26: hour 0]

    Cmax=Observed maximum plasma concentration following administration (mass/volume). The plasma samples from all patients will be assayed for eltrombopag concentrations using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS). The lower limit of quantitation (LLOQ) will be 100 ng/mL. Concentration values below the LLOQ will be reported as zero, and missing samples will be labeled accordingly

  12. Pharmacokinetic parameter-AUClast of eltrombopag when combined with cyclosporine [Week 2:hour 0,2,4,6,8 Week 4,8,12,26: hour 0]

    AUClast=Area under the curve calculated to the last quantifiable concentration point (Tlast). The plasma samples from all patients will be assayed for eltrombopag concentrations using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS). The lower limit of quantitation (LLOQ) will be 100 ng/mL. Concentration values below the LLOQ will be reported as zero, and missing samples will be labeled accordingly

  13. Pharmacokinetic parameter- AUCtau of eltrombopag when combined with cyclosporine [Week 2:hour 0,2,4,6,8 Week 4,8,12,26: hour 0]

    AUCtau=Area under the curve calculated to the end of the dosing interval ( tau). The plasma samples from all patients will be assayed for eltrombopag concentrations using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS). The lower limit of quantitation (LLOQ) will be 100 ng/mL. Concentration values below the LLOQ will be reported as zero, and missing samples will be labeled accordingly

  14. Pharmacokinetic parameter- Ctrough of eltrombopag when combined with cyclosporine [Week 2:hour 0,2,4,6,8 Week 4,8,12,26: hour 0]

    Ctrough=Pre-dose plasma concentration (mass/volume). Observed maximum plasma concentration following administration (mass/volume). The plasma samples from all patients will be assayed for eltrombopag concentrations using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS). The lower limit of quantitation (LLOQ) will be 100 ng/mL. Concentration values below the LLOQ will be reported as zero, and missing samples will be labeled accordingly

  15. Pharmacokinetic parameter- Tmax of eltrombopag when combined with cyclosporine [Week 2:hour 0,2,4,6,8 Week 4,8,12,26: hour 0]

    Tmax=The time to reach peak or maximum concentration. The plasma samples from all patients will be assayed for eltrombopag concentrations using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS). The lower limit of quantitation (LLOQ) will be 100 ng/mL. Concentration values below the LLOQ will be reported as zero, and missing samples will be labeled accordingly

  16. Pharmacokinetic parameter- CLss/F of eltrombopag when combined with cyclosporine [Week 2:hour 0,2,4,6,8 Week 4,8,12,26: hour 0]

    CLss/F=Apparent systemic (or total body) clearance at steady state from plasma. The plasma samples from all patients will be assayed for eltrombopag concentrations using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS). The lower limit of quantitation (LLOQ) will be 100 ng/mL. Concentration values below the LLOQ will be reported as zero, and missing samples will be labeled accordingly

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
  1. Patient has signed the Informed Consent (ICF) prior to any screening procedures being performed.

  2. Patient is male/female ≥18 years old at the time of informed consent and able to swallow a tablet.

  3. Patient has SAA characterized by:

  4. Bone marrow cellularity <30% (excluding lymphocytes) and

  5. At least two of the following (peripheral blood):

  • Absolute neutrophil count <500/µL

  • Platelet count <20,000/µL

  • Absolute reticulocyte count <60,000/µL

  1. Normal ECG defined as the following as determined via the mean of a triplicate ECG
  • Resting heart rate: 50-90 bpm

  • QTcF at screening <450 msec (for male patients), ≤460 msec (for female patients)

Exclusion Criteria:
  1. Diagnosis of Fanconi anemia.

  2. Evidence of a clonal hematologic bone marrow disorder on cytogenetics by central review

  3. Prior immunosuppressive therapy with cyclosporine, alemtuzumab, rabbit or horse ATG and thrombopoietin receptor (TPO-R) agonists.

    1. Hypersensitivity to eltrombopag or cyclosporine or their components. b. Contraindications to cyclospsorine.
  4. AST or ALT >3 x ULN.

  5. Serum creatinine, total bilirubin, or alkaline phosphatase >1.5 x ULN.

  6. Patient with liver cirrhosis.

    1. Infection not adequately controlled with appropriate therapy. b. Patients who are human immune deficiency virus (HIV), hepatitis C virus or hepatitis B surface antigen (HBsAg) positive. HCV-RNA negative patients are allowed to be enrolled.
  7. Moribund status or concurrent hepatic, renal, cardiac, neurologic, pulmonary, infectious, or metabolic disease of such severity that it would preclude the patient's ability to consent, be compliant with study procedures, tolerate protocol therapy, or that death within 30 days is likely.

  8. Patients with cancer who are not considered cure, are on active chemotherapeutic treatment or who take drugs with hematological effects.

  9. Administration of an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of study treatment.

  10. Pregnancy statements and contraception requirements:

Pregnancy or nursing (lactating) women Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant (or female partners of male patients), unless they are using highly effective methods of contraception during dosing and for 3 months after stopping medication.

  1. Not able to understand the investigation nature of the study or to give informed consent.

  2. Clinically significant ECG abnormality including cardiac arrhythmias (e. g. ventricular tachycardia) complete left bundle branch block, high grade atrioventricular block, or inability to determine the QTcF interval on the ECG.

  3. Presence of cardiac disease, or family history of idiopathic sudden death or congenital long QT syndrome.

  4. Risk factors for Torsades de Pointe including uncorrected hypokalemia or hypomagnesemia, or use of concomitant medication(s) with a known risk to prolong the QT interval that cannot be discontinued or replaced by safe alternative medication per www.qtdrugs.org.

  5. ECOG performance status of ≥2.

  6. Patients under the age of 40 must be referred for consideration of allogeneic bone marrow transplantation (HSCT) if (human leukocyte antigen) HLA matching has been done and a suitable matched sibling donor is available and the patient is willing to undergo transplantation (i.e. patients who do not have a HLA match or are not medically fit, not willing or unable to undergo transplantation will be considered for enrollment).

Contacts and Locations

Locations

Site City State Country Postal Code
1 Novartis Investigative Site Ribeirao Preto SP Brazil 14048-900
2 Novartis Investigative Site São Paulo SP Brazil 01323-900
3 Novartis Investigative Site Hong Kong Hong Kong
4 Novartis Investigative Site Hyderabad Telangana India 500082
5 Novartis Investigative Site Vellore India
6 Novartis Investigative Site Bologna BO Italy 40138
7 Novartis Investigative Site Brescia BR Italy 25123
8 Novartis Investigative Site Milano MI Italy 20122
9 Novartis Investigative Site Seoul Korea, Republic of 03722
10 Novartis Investigative Site Seoul Korea, Republic of 06351
11 Novartis Investigative Site Mexico D F Ciudad De Mexico Mexico 06726
12 Novartis Investigative Site Monterrey Nuevo Leon Mexico 64460
13 Novartis Investigative Site Puebla Mexico 72000
14 Novartis Investigative Site San Sebastian Pais Vasco Spain 20080
15 Novartis Investigative Site Madrid Spain 28041
16 Novartis Investigative Site Bangkok Thailand 10330
17 Novartis Investigative Site Bangkok Thailand 10700
18 Novartis Investigative Site Chiang Mai Thailand 50200
19 Novartis Investigative Site Istanbul Turkey 34890
20 Novartis Investigative Site Samsun Turkey 55139

Sponsors and Collaborators

  • Novartis Pharmaceuticals

Investigators

  • Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
Novartis Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT02998645
Other Study ID Numbers:
  • CETB115E2403
  • 2016-002814-29
First Posted:
Dec 20, 2016
Last Update Posted:
Jun 30, 2022
Last Verified:
Jun 1, 2022
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Studies a U.S. FDA-regulated Drug Product:
No
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Novartis Pharmaceuticals
Additional relevant MeSH terms:

Study Results

No Results Posted as of Jun 30, 2022