| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Steroid Refractory Chronic Graft versus Host Disease |
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| E.1.1.1 | Medical condition in easily understood language |
| Chronic Graft versus Host Disease |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
• (Phase 1b) To evaluate the safety and tolerability of multiple ascending doses of efavaleukin alfa in subjects with steroid refractory cGVHD in order to estimate the MTD and establish the RP2D
• (Phase 2) To evaluate the efficacy of efavaleukin alfa in subjects with steroid refractory cGVHD as measured by the best overall response rate (ORR) during the study according to the 2014 cGVHD National Institutes of Health (NIH) Consensus Criteria |
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| E.2.2 | Secondary objectives of the trial |
• (Phase 1b)To evaluate the immunologic effects of efavaleukin alfa including fold change from baseline in regulatory T cell (Treg), conventional T cell (Tcon), and natural killer (NK) cell numbers (cells/μL) and the Treg/Tcon ratio .
• (Phase 1b) To characterize the pharmacokinetic (PK) profile following multiple ascending subcutaneous dose administrations of efavaleukin alfa.
• (Phase 1b) To evaluate the incidence of anti efavaleukin alfa antibody formation and cross reactivity to native human IL 2.
• (Phase 2) To evaluate the safety and tolerability of efavaleukin alfa as measured by the occurrence of treatment emergent adverse events
• (Phase 2) To evaluate ORR, as defined by cGVHD NIH Consensus Criteria at various timepoints in efavaleukin alfa-treated subjects
• (Phase 2) To evaluate failure free survival (FFS), defined as absence of relapse, death, or need for additional systemic immunosuppressant cGVHD therapy
• (Phase 2)To evaluate changes in steroid use over time
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subject or legally acceptable representative has provided informed consent prior to initiation of any study specific activities/procedures.
Subject is an adult (≥ 18 years old at the time of signing the informed consent).
Subject is a recipient of an allogeneic hematopoietic stem cell transplant (HSCT).
Subject has moderate to severe steroid-refractory cGVHD as defined by all of the following criteria:
• Diagnosed with cGVHD per the 2014 cGVHD NIH Consensus Criteria
(Jagasia, 2015; Appendix 8) within the past 2 years prior to screening.
• Steroid refractory cGVHD, defined as having persistent signs and symptoms of cGVHD despite ≥ 4 weeks of prednisone (or equivalent) dosed at ≥ 0.25 mg/kg/day (or ≥ 0.5 mg/kg every other day) within the 12 months prior to screening.
• Moderate to severe cGVHD (in accordance with 2014 cGVHD NIH
Consensus Criteria [Jagasia, 2015; Appendix 9]) at screening with
involvement of at least one of the following organs at the screening and baseline visits: skin, mouth, eyes, gastrointestinal (GI) tract, liver,
lungs, and joint and fascia.
Subject has received no more than 3 previous treatments for cGVHD, excluding topical agents.
• Treatment with corticosteroids is considered a treatment for cGVHD and should be included in determining the number of previous treatments.
- Lines of therapy consisting of concurrent medications or interventions (eg, tacrolimus and corticosteroids; ECP and corticosteroids) count as 2 separate treatments.
• If cGVHD has worsened during a taper of immunosuppressive agents, restoring the agents to therapeutic level is permitted and does not count as an additional treatment.
Subject may be receiving corticosteroid therapy provided that the dose is ≤ 1 mg/kg/day of systemic prednisone or equivalent and has been stable for at least 2 weeks prior to first dose of efavaleukin alfa.
Subject may be receiving other non-corticosteroid immunosuppressive
therapies provided that the immunosuppressant dose is stable for at least 2 weeks prior to first dose of efavaleukin alfa. Adjustments to dose of calcineurin inhibitor or sirolimus are allowed only to maintain drug levels within therapeutic range.
Subject has a Karnofsky performance status score ≥ 50%.
Subject has an estimated life expectancy of > 3 months.
Subjects must have adequate hepatic function:
• total bilirubin < 2.0 mg/dL (34.2 µmol/L) - exception permitted in participants with Gilbert's Syndrome
• aspartate transaminase [AST; SGOT]/Alanine transaminase [ALT; SGPT] ≤ 2x upper limit of normal (ULN), unless hepatic dysfunction is a manifestation of presumed cGVHD.
• abnormal LFTs in the context of active cGVHD involving other organ systems may also be permitted if the treating physician documents the abnormal LFTs as being consistent with hepatic cGVHD. If LFT abnormalities are deemed consistent with hepatic cGVHD by the investigator, a liver biopsy will not be mandated.
Subjects must have adequate pulmonary function defined as: forced expiratory volume in 1 second (FEV1) ≥ 50% or hemoglobin-adjusted diffusion capacity for carbon monoxide (DLCO Hb) ≥ 40% of predicted, unless pulmonary dysfunction is deemed to be due to cGVHD.
Subjects must have adequate renal function defined as: a calculated glomerular filtration rate of > 50 mL/min/1.73 m2 using the MDRD formula.
Subjects must have adequate cardiac function defined as:: no history within 6 months prior to screening of myocardial infarction, unstable angina, New York Heart Associate Class III or IV heart failure, or stroke. No findings on the screening electrocardiogram (ECG) that in the opinion of the investigator requires further cardiovascular evaluation, including severe uncontrolled ventricular arrhythmias, electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Any ECG abnormality at screening must be documented by the investigator as not clinically significant prior to enrollment into the study.
Subjects must have adequate bone marrow function indicated by ANC > 1.00 x 109/L and platelets > 50 x 109/L without growth factors or transfusions within the 4 weeks prior to starting efavaleukin alfa.
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| E.4 | Principal exclusion criteria |
Subject is concurrently receiving treatment with calcineurin-inhibitor plus sirolimus
Subject has received ibrutinib, imatinib, bortezomib, entospletinib, ruxolitinib or other JAK inhibitor, or treatment with any investigational drug or device within 4 weeks prior to starting efavaleukin alfa.
Subject has received the following therapies considered investigational for treament of cGVHD: imatinib, ibrutinib, bortezomib, ruxolitnib, entospletinib, within 4 weeks prior to enrollment or is currently receiving treatment in another investigational drug or device study.
Subject has received treatment with T-cell depleting, B-cell depleting or IL-2 signaling targeted medication
Subject has received treatment with T regulatory cell expanding therapies (ie ECP, PUVA, UVB, adoptively transferred T regulatory cells) within 4 weeks prior to starting efavaleukin alfa.
Subject has received a donor lymphocyte infusion within 12 weeks prior to starting efavaleukin alfa.
Subject with active morphologic relapse/progression of hematologic malignancy post transplantation. Persistent CLL early after transplantation that subsequently entered remission will not be excluded.
Subject has a history of malignancy, other than the indication for hematopoietic cell transplantation, with the following exceptions:
• adequately treated nonmelanoma skin cancers without current evidence of disease
• adequately treated cervical carcinoma in situ without current evidence of disease
• adequately treated breast ductal cancer in situ without current evidence of disease
• any malignancy treated with curative intent and with no evidence of active disease present for more than 5 years prior to screening and felt to be at low risk for recurrence by the treating physician.
Subject has a history of thrombotic microangiopathy, hemolytic-uremic syndrome or thrombotic thrombocytopenic purpura.
Subject has an active infection requiring treatment with IV antibiotics or has been hospitalized for treatment of an active infection in the 4 weeks prior to starting efavaleukin alfa.
Subject has known history of active tuberculosis.
Subject has a positive test for tuberculosis during screening defined as either:
• positive purified derivative (PPD) (≥ 5 mm of induration at 48 to 72 hours after test is placed)
OR
• positive Quantiferon or T-SPOT test
• subjects with a positive PPD and a history of Bacillus Calmette-Guérin vaccination are allowed with a negative Quantiferon test and negative chest x ray
• subjects with a positive PPD test (without a history of Bacillus Calmette-Guérin vaccination) or subjects with a positive or indeterminate Quantiferon test are allowed if they have ALL of the following at screening:
o no symptoms per tuberculosis worksheet provided by Amgen
o document history of a completed course of adequate prophylaxis (completed treatment for latent tuberculosis [TB] per local standard of care prior to the start of investigational product
o no known exposure to a case of active tuberculosis after most recent prophylaxis
o negative chest X-ray
Subject is positive for hepatitis B surface antigen, hepatitis B core antibody (confirmed by hepatitis B deoxyribonucleic acid [DNA] polymerase chain reaction [PCR] test) or detectable hepatitis C virus ribonucleic acid (RNA) by PCR (screening is generally done by hepatitis C antibody [HepCAb], followed by hepatitis C virus RNA by PCR if HepCAb is positive). Subjects with a history of hepatitis B vaccination without history of hepatitis B are allowed.
Subject has positive test results for Human Immunodeficiency Virus (HIV) or known to be HIV positive.
Phase 1b subject has a drug or alcohol urine test positive for illicit drugs at the screening visit. Prescription medications detected by the drug test are
allowed if they are being taken under the direction of a physician.
Phase 1b subjects can not be a current smoker, nor have used any nicotine or tobacco containing products within the last 6 months prior to screening.
Phase 1b subject is unable to avoid alcohol or tobacco consumption for the duration of the study.
Subject has known sensitivity to efavaleukin alfa or its excipients to be administered during dosing.
Subject likely to be unable to complete all protocol required study visits or procedures, and/or to comply with all required study procedures to the best of the subject and investigator’s knowledge.
History or evidence of any other clinically significant disorder, condition, or disease
Females who are pregnant or breastfeeding, or planning to become pregnant or breastfeed during treatment and for an additional 6 weeks after the last dose of efavaleukin alfa.
Females of child bearing potential with a positive pregnancy test
Females of childbearing potential who are unwilling to use 1 highly effective method of contraception during treatment and for an additional 6 weeks after receiving the last dose of efavaleukin alfa. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1b
- Incidence of dose limiting toxicities (DLTs) at first 4 weeks
- Incidence of dose limiting toxicities (DLTs) at first 4 weeks
- Incidence of all treatment related and treatment emergent adverse events and serious adverse events
Phase 2
- Best ORR defined as the proportion of subjects achieving a Complete Response (CR) or Partial Response (PR) at any visit during the study according to the 2014 cGVHD NIH Consensus Criteria |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Phase 1b
- Fold changes from baseline of Treg absolute cell counts (cells/μL), after efavaleukin alfa administration.
- Fold changes from baseline of Tcon and NK absolute cell counts (cells/μL), after efavaleukin alfa administration.
- Efavaleukin alfa serum concentration and PK parameters including, but not limited to, maximum observed concentration (Cmax), the time of maximum observed concentration (Tmax), and the area under the concentration-time curve over a dosing interval (AUCtau) after the first and week 4 doses
- Subject incidence of anti efavaleukin alfa binding antibodies and cross reactivity to IL 2
- Subject incidence of anti efavaleukin alfa and anti IL 2 neutralizing antibodies
Phase 2
- Treatment-emergent and treatment-related adverse events and serious adverse events throughout the study
- ORR at 8, 16, 24, 36, and 52 weeks
- Time to first response
- Duration of response
- FFS at 52 weeks
- Steroid use over time as compared to baseline
- Changes in Lee Symptom Score over time
- Changes in SF36v over time
- Changes in Karnofsky performance status over time
- Efavaleukin alfa plasma concentration and PK parameters including, but not limited to, maximum observed concentration (Cmax), the time of maximum observed concentration (Tmax), and AUCtau after the first and last doses and AUC from time 0 to the time of the last quantifiable sample (AUClast).
- Subject incidence of anti efavaleukin alfa binding antobidies and cross-reactivity to IL 2
- Subject incidence of anti efavaleukin alfa and anti IL 2 neutralizing antibodies |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United States |
| Belgium |
| France |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
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