Early phase II study of Azacitidine and Carboplatin priming for Avelumab in patients with advanced melanoma who are resistant to immunotherapy.

Phase 2

• Conditions: Metastatic melanoma; Cancer - Malignant melanoma; Immunotherapy resistant

• Registration Number: ACTRN12618000053224
• Lead Sponsor: niversity of Newastle

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2018-01-16
• Last Update Posted: 28 November 2022

Recruitment & Eligibility

• Status: Stopped early
• Sex: All
• Target Recruitment: 20

Inclusion Criteria

•Unresectable or metastatic melanoma
•Primary resistance to previous anti-PD1 immunotherapy
•Male or Female subjects aged>= 18 years
•Before study enrolment written informed consent to participate in the trial must be given according to ICH/GCP and national/local regulations
•Adequate haematological function defined by absolute neutrophil count (ANC) > 1.5 x 109/L, platelet count) > 100 x 109/L, and haemoglobin) > 9g/dL (may have been transfused)
•Adequate hepatic function defined by a total bilirubin level <1.5 x the upper limit of normal (ULN) range and AST and ALT levels <2.5 x ULN for all subjects
•Adequate renal function defined by an estimated creatinine clearance of greater than 30mL/min according to the Cockcroft-Gault formula or local institutional method
•Tumour material is mandatory for subcutaneous or lymph node disease - tumour tissue selected must not be previously irradiated; treatment should start only after complete wound healing from surgery
•Disease status before first treatment should be documented by full CT scan of chest, abdomen and pelvis and MRI brain. PET scans will also be done before first treatment to help with monitoring disease response in subcutaneous/ lymph node metastases
•BRAF mutation status
•ECOG Performance Status 0,1,2
•Patient is not currently participating and receiving study therapy or has not participated in a study of an investigational agent and received study therapy or used and investigation device within 4 weeks prior to first dose of treatment
•Women of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to the first dose of study treatment
•Effective contraception for both male and female subjects if the risk of conception exists (Note: The effects of the trial drug on the developing human fetus are unknown; thus, women of childbearing potential and men must agree to use effective contraception, defined as 2 barrier methods, or 1 barrier method with a spermicide, an intrauterine device, or use of oral
•female contraceptive. Effective contraception must be used 30 days prior to first trial drug administration, for the duration of trial participation, and at least for 30 days after stopping trial participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this trial, the treating physician should be informed immediately.
•[For female participants] If you do become pregnant whilst participating in the research project, you should advise your study doctor immediately. Your study doctor will withdraw you from the research project and advise on further medical attention should this be necessary. You must not continue in the research if you become pregnant.
•[For male participants] You should advise your study doctor if you father a child while participating in the research project. Your study doctor will advise on medical attention for your partner should this be necessary.
•Female patients who are breast feeding should discontinue nursing prior to the first dose of study treatment and until 120 days after the last dose of the study drug
•Aboriginal Torres Strait Islander patients must be offered the option of having the Aboriginal Liaison Officer or a friend/relative be present during consenting process
•Patients with a primary language other than English must be offered an interpreter during the consenting process.

Exclusion Criteria

•Mucosal or ocular melanoma
•All subjects with brain metastases, except those meeting the following criteria:
- Brain metastases that have been treated locally and are clinically stable for at least 2 weeks prior to enrollment
- No ongoing neurological symptoms that are related to the brain localization of the disease (sequelae that are a consequence of the treatment of the brain metastases are acceptable)
- Subjects must be either off steroids or on a stable or decreasing dose of <10mg daily prednisone (or equivalent)
•Prior organ transplantation, including allogenic stem-cell transplantation
•Diagnosis of immunodeficiency
•History of HIV; positive test for HBV surface antigen and/or confirmatory HCV RNA (if anti-HCV antibody tested positive) or any other significant acute or chronic infections
•Systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment
•Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent:
-Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible
-Subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses 10 mg equivalent prednisone per day
-Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable
•Known severe hypersensitivity reactions to monoclonal antibodies (Grade >3 NCI-CTCAE v4.03), any history of anaphylaxis, or uncontrolled asthma (3 or more features of partially controlled asthma)
•Persisting toxicity related to prior therapy of Grade>1 NCI-CTCAE v 4.03, alopecia and sensory neuropathy Grade <2 is acceptable
•Active infections requiring systemic therapy
•Significant cardiovascular disease i.e uncontrolled hypertension/angina/heart failure/arrhythmias
•History of immune related toxicity to previous immunotherapy of grade 2 or higher except endocrinology related toxicity that is treated and stable and on replacement therapy for adrenal, pituitary or thyroid deficiency (thyroxine, insulin or physiologic corticosteroid therapy allowed). Subjects requiring hormone replacement with corticosteroids are eligible if the steroid are administered only for the purpose of hormonal replacement and at doses less or equal to 10 mg or 10 mg equivalent prednisone per day. Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intra-ocular, or inhalation) are acceptable
•Patients who received treatment with live vaccines within 30 days prior to first dose of study medication
•History of hematologic or primary solid tumour malignancy, unless no evidence of that disease for 3 years
•Pregnancy or lactation
•Known alcohol or drug use
•Any psychiatric condition that would prohibit the understanding or rendering of informed consent
•Vaccination within 4 weeks of the first dose of avelumab and while on trial is prohibited except for administration of inactivated vaccines

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Quantify response as complete response (CR), partial response (PR) or stable disease (SD) according to RECIST 1.1 [Week 9 - after 2 cycles of azacitidine/carboplatin;<br>];Quantify response as complete response (CR), partial response (PR) or stable disease (SD) according to RECIST 1.1 [Week 22 - after 6 cycles of immunotherapy (Avelumab) ];Determine overall response rate (ORR) according to irRECIST[Week 9 - after 2 cycles of azacitidine/carboplatin;<br>Week 22 - after 6 cycles of immunotherapy (Avelumab) ]