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WithdrawnPhase 1ACTRN12617001621303

Novel Triple Combination Immunotherapy for Patients with Metastatic Melanoma

FLIGHT Protocol: An Open Label Phase 1 Study Investigating the Effects of CDX-301 on the Safety, Clinical Activity, and Immune Priming of Glembatumumab Vedotin Combined with Pembrolizumab or Nivolumab in Unresectable or Metastatic Melanoma Patients Not Responding to the Anti-PD1 Therapy

Sponsor

Central Adelaide Local Health Network

Enrollment

18 participants

Start Date

Feb 4, 2018

Study Type

Interventional

Conditions

Metastatic Melanoma not responding to Anti-PD1 Therapy

Summary

The aim of this project is to investigate the effects of CDX-301 on the safety, clinical activity, and immune priming of glembatumumab vedotin combined with pembrolizumab or nivolumab in adult patients with locally advanced or metastatic melanoma. Who is it for? You may be eligible to join this study if you are aged 18 years or over and have unresectable, histologically confirmed Stage 3 or 4 melanoma not responding to pembrolizumab or nivolumab treatment. Study details: All participants will receive CDX-301 and glembatumumab vedotin in combination with either pembrolizumab or nivolumab. CDX-301 is administered by subcutaneous injection, whereas glembatumumab vedotin, pembrolizumab and nivolumab are administered intravenously, i.e. directly into the vein. CDX-301 will be given on Days -6 to -2 of a 3-weekly study cycle, for a total of two cycles. Glembatumumab Vedotin will be given on day 1 of each 3-weekly study cycle. In addition patients will receive either Pembrolizumab on day 1 of each cycle every 3 weeks OR Nivolumab every 2 weeks. Participants continue with Glembatumumab Vedotin, Pembrolizumab or Nivolumab, unless there is protocol-defined progression of disease or intolerance of one or more of these drugs We will collect blood samples from your vein before you receive the study treatments and between each of the study treatments. These blood samples will be analysed in the laboratory for the presence and character of specialised white blood cells, which may have been mobilised into the blood by the CDX-301 and glembatumumab vedotin treatment. A sample of your original melanoma biopsy tissue may be compared with additional (optional) melanoma tissue biopsies taken during the course of the study. These melanoma samples will be examined in the laboratory for evidence of any new immune reaction that may be caused by the action of CDX-301 and glembatumumab vedotin. This study will help in determining whether CDX-301 is safe to administer in combination with glembatumumab vedotin and with either pembrolizumab or nivolumab. .

Eligibility

Sex: Both males and femalesMin Age: 18 Yearss

Inclusion Criteria27

  • Adults aged greater than or equal to 18 years
  • Signed written, informed consent
  • Unresectable, histologically confirmed Stage 3 or 4 cutaneous, mucosal or ocular melanoma as per AJCC 8th edition melanoma staging system regardless of BRAF mutation status
  • Not responding while on Pembrolizumab or Nivolumab treatment with documented progressive disease based on radiographic assessment by RECIST v1.1, and confirmed from 2 scans at least 4 weeks apart; the investigator deems it appropriate to continue treatment with the anti-PD1 therapy beyond confirmed disease progression
  • For patients with V600 BRAF mutation, prior BRAF ± MEK inhibitor therapy is required, unless contraindicated or not tolerated according to the TGA approved product information, and the condition must not be responding during current treatment with Pembrolizumab or Nivolumab
  • May be receiving Nivolumab and experience disease progression after previous treatment with Nivolumab in combination with induction ipilimumab
  • May have recommenced Pembrolizumab or Nivolumab after previous response and subsequent progression and meet inclusion criterion #4
  • As initial PBS-listed treatment, Pembrolizumab or Nivolumab must not exceed a total of 6 or 9 doses, respectively, and for continuing PBS-listed treatment with Pembrolizumab or Nivolumab, patients must have stable or responding disease
  • Pre-treatment tumour tissue is available
  • Measurable disease by RECIST v1.1; target lesions selected for tumour measurements should exclude previously irradiated lesions and should be those where additional (e.g. palliative) treatments are not indicated or anticipated
  • ECOG performance status 0 to 2
  • Life expectancy of at least 12 weeks as estimated by the investigator
  • Resolution of toxicities related to prior therapies (including radiotherapy) to NCI CTCAE grade 1 severity, except for alopecia, grade 2 fatigue, vitiligo, or endocrinopathies on replacement therapy
  • Adequate bone marrow, liver, and renal function
  • a. Absolute neutrophil count greater than or equal to 1.5 x 109/L;
  • b. Platelet count greater than or equal to 100 x109/L;
  • c. Haemoglobin greater than or equal to 90 g/L;
  • d. Serum bilirubin 'less than or equal to 1.5 x upper limit of normal (ULN); with the exception of patients with known Gilbert’s syndrome
  • e. In the absence of metastasis, liver transaminase levels 'less than or equal to3 x ULN;
  • f. In the presence of metastasis, liver transaminase levels 'less than or equal to 5 x ULN
  • g. Creatinine clearance of 'greater than or equal to' 40 mL/min calculated by Cockcroft-Gault
  • Women of child-bearing potential must have a negative serum pregnancy test at screening, and a negative urine pregnancy test prior to dosing at each treatment course. In addition, they must agree to use any of the following contraceptive methods from 14 days prior to commencing study treatment, throughout the entire treatment period, and for 4 months following discontinuation of treatment:
  • a. Intrauterine device with a documented failure rate of <1% per year;
  • b. Vasectomized partner who is sterile prior to the patient’s entry and is the sole sexual partner;
  • c. Double barrier contraception defined as condom with spermicidal jelly, foam, suppository, or film; or diaphragm with spermicide; or male condom and diaphragm;
  • d. Complete abstinence from sexual intercourse where the lifestyle of the patient ensures compliance;
  • Fertile male patients must use an effective method of contraception during treatment and for 4 months following discontinuation of treatment

Exclusion Criteria15

  • Previously received GV or any other monomethyl auristatin E (MMAE)-containing agents
  • Subjects with a history of allergic reactions attributed to compounds of similar composition to dolastatin or auristatin. Compounds of similar composition include Auristatin PHE as an anti-fungal agent, Auristatin PE (TZT-1027, Soblidotin, NSC-654663) and symplostatin 1 as an anti-tumour agent
  • greater than or equal to grade 2 neuropathy
  • Active, untreated central nervous system metastases, except for asymptomatic lesions where treatment is not indicated. Otherwise, patients with brain metastases identified at screening may be rescreened after the lesion(s) have been appropriately treated; patients with treated brain metastases should be neurologically stable for 2 weeks post-treatment and before study enrolment, and off corticosteroids for at least 2 weeks before administration of study drugs
  • Evidence of severe or uncontrolled systemic disease (e.g. acute infection requiring treatment with intravenous (IV) antibiotics, unstable or decompensated cardiac disease including life-threatening arrhythmias, respiratory, hepatic, and renal disease). During the screening period, oral antibiotic therapy will be limited to documented infection but will not be exclusionary
  • Known alcohol or drug abuse
  • Active autoimmune disease or other conditions requiring systemic steroids or immunosuppressive medications, except for patients with vitiligo, endocrinopathies, type 1 diabetes, or patients with resolved childhood asthma/atopy or other syndromes which would not be expected to recur in the absence of an external trigger (e.g., drug-related serum sickness or post-streptococcal glomerulonephritis). Subjects with mild asthma who require intermittent use of bronchodilators (such as salbutamol) who have not been hospitalized for asthma in the preceding 3 years will not be excluded from this study.
  • Treatment with immunosuppressive medications within 4 weeks or corticosteroids within 2 weeks. The use of prednisone or equivalent <0.125 mg/kg/day (absolute maximum of 10 mg/day) as replacement therapy is permitted. Inhaled and topical corticosteroids are permitted.
  • Evidence of active infection with HIV, hepatitis B or C
  • Patients with interstitial lung disease or history of pneumonitis requiring treatment with steroids
  • History of pulmonary disease (i.e. COPD emphysema or chronic bronchitis with FEV1 <60% predicted); pulmonary function tests are required in patients with prolonged smoking history or symptoms of respiratory dysfunction
  • Patients with acute diverticulitis
  • Pregnant or breast-feeding females
  • Patients who received live vaccines within 30 days prior to study (e.g. measles, mumps, rubella, chicken pox, shingles, yellow fever, seasonal flu, H1N1 flu, rabies, BCG, and typhoid vaccine). Inactivated influenza vaccination may be permitted during the flu season and the preferred time is 7-14 days after CDX-301 administration
  • Any underlying medical condition that, in the investigator’s opinion, will make the administration of GV or CDX-301 hazardous to the patient, or would obscure the interpretation of toxicity determination or adverse events

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Interventions

CDX-301: 10-75 micrograms/kg/day subcutaneously: • Given in an accelerated titration design for cohorts 1-2 (In the accelerated titration design, one participant is recruited to each one of the two

CDX-301: 10-75 micrograms/kg/day subcutaneously: • Given in an accelerated titration design for cohorts 1-2 (In the accelerated titration design, one participant is recruited to each one of the two dose escalation cohorts. The dose escalation is for CDX-301 only. Anti-PD1 therapy is given according to TGA/PBS approved doses and Glembatumumab Vedotin is given at 1.9mg/kg every 21 days. The CDX-301 dose escalation comprises for cohort 1, a first 21-day cycle of CDX-301 at 10mcg/kg then a second 21-day cycle of CDX-301 at 25mcg/kg. Similarly, for cohort 2, a first 21-day cycle of CDX-301 at 25mcg/kg then a second 21-day cycle of CDX-301 at 75mcg/kg. There is a 21-day observation period for treatment related toxicity (TLT) and another participant is not enrolled until that TLT assessment has been made.) All participants will receive CDX-301 and Glembatumumab Vedotin plus either Pembrolizumab or Nivolumab. • CDX-301 Given on Days -6 to -2 of a 3-weekly study cycle • First and second cycle only of 3-weekly study cycles Glembatumumab Vedotin: 1.9 mg/kg IV infusion over 90 minutes on day 1 of each 3-weekly study cycle Pembrolizumab : 2mg/kg IV infusion on day 1 of each cycle every 3 weeks Nivolumab: 3mg/kg IV infusion every 2 weeks, which may coincide with day 1 of each 3-weekly study cycle Participants continue with Glembatumumab Vedotin, Pembrolizumab or Nivolumab, unless there is protocol-defined progression of disease or intolerance of one or more of these drugs. Participants will receive Pembrolizumab or Nivolumab depending on whether this was the anti-PD1 therapy they received upon study entry.

Locations(1)

The Royal Adelaide Hospital - Adelaide

SA, Australia

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ACTRN12617001621303