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Trial registered on ANZCTR


Registration number
ACTRN12617001621303
Ethics application status
Approved
Date submitted
23/10/2017
Date registered
11/12/2017
Date last updated
11/12/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Novel Triple Combination Immunotherapy for Patients with Metastatic Melanoma
Scientific title
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
Secondary ID [1] 293163 0
None
Universal Trial Number (UTN)
Trial acronym
FLIGHT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Unresectable Metastatic Melanoma 305143 0
Metastatic Melanoma not responding to Anti-PD1 Therapy 305144 0
Condition category
Condition code
Cancer 304464 304464 0 0
Malignant melanoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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.
Intervention code [1] 299411 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 303704 0
To evaluate the safety of CDX-301 when combined with Glembatumumab Vedotin, and Pembrolizumab or Nivolumab in patients with unresectable or metastatic melanoma. Safety parameters will be assessed at baseline and at study visits and include clinically relevant changes in vital signs, adverse events, physical examination, complete blood count, MBA20, urinalysis, 12-lead ECG.
Pembrolizumab or Nivolumab
The list below summarises the side effects from these anti-PD1 drugs.

• Very common side effects seen in greater than or equal to 20% (or 1 in 5) of participants:
o Itching of the skin
o Loose or watery stools
o Cough

• Common side effects seen in greater than or equal to 10% (or 1 in 10) to less than 20% (or 1 in 5) of participants:
o Joint pains
o Back pains
o Fever – Temperature greater than or equal to 38 degrees Celsius
o Rash
o Fatigue

• Common side effects seen in greater than or equal to 1% (or 1 in 100) to less than 10% (or 1 in 10) of participants:
o Not enough thyroid hormone so you may feel tired, gain weight, feel cold, have infrequent or hard stools (constipation)
o Too much thyroid hormone so you may feel anxious, angry, can’t sleep, weak, tremble, sweat, tired, have loose and watery stools (diarrhoea)
o Pneumonitis* - inflammation of the lungs so you may feel short of breath and cough. Rarely this might lead to death.
o Inflammation of the mouth
o Inflammation of the bowels/gut that may cause pain in your belly with loose or watery stools
o Inflammation of the skin so you may have peeling of the skin, itching, skin redness
o Dry skin
o Dry mouth
o Headaches
o Chills
o Nausea
o Vomiting
o Decreased appetite
o Pain in your belly
o Loss of skin colour
o Muscle and bone pain
o Low level of salt in the blood that may cause you to feel tired, confused, headache, muscle cramps or sick to your stomach
o Dizziness or fainting (low blood pressure), flushing, rash, fever, shortness of breath or sick to your stomach at the time of receiving your IV infusion or just after, or pain at the site of infusion.
o Tingling, burning, numbness or weakness possibly in arms, legs, hands and/or feet
o Increased alkaline phosphatase - a lab test result associated with liver or bone abnormalities
o Increased amylase – a lab test result associated with pancreas inflammation
o Increased ALT/AST – lab test result associated with abnormal liver function
o Increased creatinine – a lab test result associated with decreased kidney function
o Increased lipase – a lab result associated with pancreas inflammation

• Immune-mediated serious side effects seen in greater than or equal to 0.1% (or 1 in 1000) to less than 1% (or 1 in 100) of participants:
o Inflammation of the skin so you may have widespread peeling of the skin, itching and skin redness. More severe skin reactions may involve the inside of your mouth, the surface of your eye and genital areas, and/or may cause the top layer of your skin to peel from all over your body which can cause severe infection. Rarely these reactions lead to death.
o Inflammation of the liver that may cause a poor appetite, feeling tired, mild fever, muscle or joint aches, sick to your stomach and vomiting, pain in your belly, yellow eyes and skin, and dark urine
o Inflammation of the pituitary gland (a gland in the head), which may cause headaches, sick to your stomach, changes in behaviour, double vision, few to no menstrual cycles, weakness, vomiting and dizziness or fainting.
o Adrenal glands (glands on top of the kidneys) may not make enough hormone causing tiredness, weight loss, muscle weakness, feeling faint, joint, muscle and abdominal aches, nausea, vomiting, loose or watery stools, fever, salt craving, and sometimes darkening of the skin like a suntan.
o Inflammation of the kidney so you may pass less urine or have cloudy or bloody urine, swelling and low back pain, or kidney failure
o Inflammation of the muscles so you may feel weak or pain in the muscles
o Inflammation of the pancreas (a gland in your abdomen that makes digestive enzymes) so you may have severe pain in the top part of your belly that may move to the back, sick to your stomach, and vomiting that gets worse when you eat
o Inflammation of the pancreas (a gland in your abdomen that controls sugar levels) so you may have too much sugar in your blood (diabetes), and you may feel thirsty, and may be likely to need regular insulin shots
o Inflammation of the eye so you may have redness of the eye, blurred vision, sensitive to light, have eye pain, see floaters or have headaches
o Inflammation of the nerves that may cause pain, weakness or tingling in the hands and feet, and may spread to the legs, arms and upper body leading to severe muscle weakness and possible temporary paralysis.
o Inflammation of the middle layer of your heart wall (myocarditis) that may cause your heart to have difficulty pumping blood throughout your body, which can cause chest pain, shortness of breath and swelling of the legs. You may experience a fast or irregular heartbeat that may cause dizziness or fainting. Sometimes this condition can lead to death.
Timepoint [1] 303704 0
Participant assessed during the following time points throughout 24 months of study duration: Cycles 1 & 2: Day -6 to Day -2, Days 1, 3 & 8, then Day 1 of following Cycles, End of treatment visit within 28 days post last dose of study drug, then every 12 weeks until study closure
Secondary outcome [1] 339913 0
To assess response to treatment by Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 and immune-related RECIST (irRECIST).

Outcome assessments and definitions are inherent in these response criteria and described according to the following response categories: complete response, partial response, stable disease or progressive disease.
Timepoint [1] 339913 0
Participant assessed during the following time points throughout 24 months of study duration: Cycles 1 & 2: Day -6 to Day -2, Days 1, 3 & 8, then Day 1 of following Cycles, End of treatment visit within 28 days post last dose of study drug, then every 12 weeks until study closure
Secondary outcome [2] 340148 0
To assess the time to response
The time to response is defined as the time elapsed between study treatment initiation and RECIST-defined complete response or partial response.

Timepoint [2] 340148 0
Participant assessed during the following time points throughout 24 months of study duration: Cycles 1 & 2: Day -6 to Day -2, Days 1, 3 & 8, then Day 1 of following Cycles. End of treatment visit within 28 days post last dose of study drug, then every 12 weeks until study closure
Secondary outcome [3] 340149 0
To assess the time to next treatment (TTNT)
The time to next treatment (TTNT) is defined as the time elapsed between study treatment initiation and initiation of the next line of anti-cancer treatment.

Timepoint [3] 340149 0
Participant assessed during the following time points throughout 24 months of study duration: Cycles 1 & 2: Day -6 to Day -2, Days 1, 3 & 8, then Day 1 of following Cycles, End of treatment visit within 28 days post last dose of study drug, then every 12 weeks until study closure
Secondary outcome [4] 340150 0
To assess progression free survival (PFS)
Progression-free survival (PFS) is defined as the time elapsed between study treatment initiation and tumour progression or death from any cause.
Timepoint [4] 340150 0
Participant assessed during the following time points throughout 24 months of study duration: Cycles 1 & 2: Day -6 to Day -2, Days 1, 3 & 8, then Day 1 of following Cycles, End of treatment visit within 28 days post last dose of study drug, then every 12 weeks until study closure
Secondary outcome [5] 340151 0
To evaluate immunogenicity to CDX-301 and GV
Immunogenicity is defined as the laboratory detection above background of serum antibodies specific for CDX-301 or GV.
Timepoint [5] 340151 0
Participant assessed during the following time points throughout 24 months of study duration: Cycles 1 & 2: Day -6 to Day -2, Days 1, 3 & 8, then Day 1 of following Cycles, End of treatment visit within 28 days post last dose of study drug, then every 12 weeks until study closure
Secondary outcome [6] 340676 0
To assess the duration of response
The duration of response is defined as the time that a RECIST-defined complete response or partial response is maintained.
Timepoint [6] 340676 0
Participant assessed during the following time points throughout 24 months of study duration: Cycles 1 & 2: Day -6 to Day -2, Days 1, 3 & 8, then Day 1 of following Cycles. End of treatment visit within 28 days post last dose of study drug, then every 12 weeks until study closure

Eligibility
Key inclusion criteria
Inclusion Criteria: patients must meet all of the following criteria to be eligible for the study

1. Adults aged greater than or equal to 18 years
2. Signed written, informed consent
3. 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
4. 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
5. 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
6. May be receiving Nivolumab and experience disease progression after previous treatment with Nivolumab in combination with induction ipilimumab
7. May have recommenced Pembrolizumab or Nivolumab after previous response and subsequent progression and meet inclusion criterion #4
8. 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
9. Pre-treatment tumour tissue is available
10. 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
11. ECOG performance status 0 to 2
12. Life expectancy of at least 12 weeks as estimated by the investigator
13. 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
14. 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
15. 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;
16. Fertile male patients must use an effective method of contraception during treatment and for 4 months following discontinuation of treatment
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion Criteria: patients who meet any of the following conditions are NOT eligible for the study
1. Previously received GV or any other monomethyl auristatin E (MMAE)-containing agents
2. 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
3. greater than or equal to grade 2 neuropathy
4. 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
5. 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
6. Known alcohol or drug abuse
7. 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.
8. 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.
9. Evidence of active infection with HIV, hepatitis B or C
10. Patients with interstitial lung disease or history of pneumonitis requiring treatment with steroids
11. 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
12. Patients with acute diverticulitis
13. Pregnant or breast-feeding females
14. 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
15. 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
accelerated dose titration design
Phase
Phase 1
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
descriptive statistics

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 9222 0
The Royal Adelaide Hospital - Adelaide
Recruitment postcode(s) [1] 17878 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 297792 0
Commercial sector/Industry
Name [1] 297792 0
Celldex Therapeutics, Inc
Address [1] 297792 0
53 Frontage Road,
Suite 220,
Hampton, NJ08827
Country [1] 297792 0
United States of America
Primary sponsor type
Government body
Name
Central Adelaide Local Health Network
Address
Port Road,
Adelaide
South Australia 5000.
Country
Australia
Secondary sponsor category [1] 296830 0
None
Name [1] 296830 0
Address [1] 296830 0
Country [1] 296830 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298850 0
Royal Adelaide Hospital HREC
Ethics committee address [1] 298850 0
Port Road,
Adelaide
South Australia, 5000
Ethics committee country [1] 298850 0
Australia
Date submitted for ethics approval [1] 298850 0
24/07/2017
Approval date [1] 298850 0
13/10/2017
Ethics approval number [1] 298850 0
R20170717

Summary
Brief 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. .
Trial website
Trial related presentations / publications
None as yet
Public notes
None

Contacts
Principal investigator
Name 78438 0
Prof Michael P Brown
Address 78438 0
Royal Adelaide Hospital,
Medical Oncology Department,
Level 6E.351
Port Road,
Adelaide, SA. 5000
Country 78438 0
Australia
Phone 78438 0
+61 8 70742335
Fax 78438 0
+61 8 70746211
Email 78438 0
michaelp.brown@sa.gov.au
Contact person for public queries
Name 78439 0
Mrs Anne Milton
Address 78439 0
Royal Adelaide Hospital,
Cancer Clinical Trials Unit,
Level 6E.351
Port Road,
Adelaide, SA. 5000
Country 78439 0
Australia
Phone 78439 0
+61 8 707 42342
Fax 78439 0
+61 8 70746211
Email 78439 0
anne.milton@sa.gov.au
Contact person for scientific queries
Name 78440 0
Prof Michael P Brown
Address 78440 0
Royal Adelaide Hospital,
Medical Oncology Department
Level 6E.351
Port Road, Adelaide, SA. 5000
Country 78440 0
Australia
Phone 78440 0
61 8 70742335
Fax 78440 0
+61 8 70746211
Email 78440 0
michaelp.brown@sa.gov.au

No data has been provided for results reporting
Summary results
Not applicable