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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT04834973
Registration number
NCT04834973
Ethics application status
Date submitted
29/03/2021
Date registered
8/04/2021
Date last updated
18/04/2023
Titles & IDs
Public title
A Trial of Tigilanol Tiglate in Combination With Pembrolizumab in Stage IIIB to IV M1c-melanoma
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Scientific title
A Phase Ib/IIa, Dose-escalation Study to Evaluate the Safety, Tolerability, and Preliminary Effectiveness of Intratumoural Tigilanol Tiglate in Combination With Intravenous Pembrolizumab in Adults With Stage IIIb to IV M1c-melanoma
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Secondary ID [1]
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KN-B16
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Secondary ID [2]
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QB46C-H06
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Melanoma
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Condition category
Condition code
Cancer
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Malignant melanoma
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - tigilanol tiglate
Treatment: Drugs - pembrolizumab
Experimental: Single arm open label - Single or multiple Intratumoural treatment of tigilanol tiglate at escalating doses of 0.6 mg/m2, 1.2 mg/m2 and 2.4 mg/m2 given every 28 days (+1 to 14days) in combination with three weekly 200 mg intravenous doses of pembrolizumab.
Treatment: Drugs: tigilanol tiglate
Single or multiple Intratumoural treatment of tigilanol tiglate at escalating doses of 0.6 mg/m2, 1.2 mg/m2 and 2.4 mg/m2.
Tigilanol tiglate is a novel, short-chain diterpene ester in early clinical development for local treatment of a wide range of solid tumours.
Treatment: Drugs: pembrolizumab
Three weekly 200 mg intravenous pembrolizumab treatment.
Pembrolizumab is a systemic anti-programmed cell death receptor 1 (PD 1) immunotherapy.
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Determine Dose Level
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Assessment method [1]
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To determine the dose level of intratumoural tigilanol tiglate when administered in combination with pembrolizumab (200 mg IV) at which there is no dose-limiting toxicity (DLT) recorded.
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Timepoint [1]
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12 months
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Primary outcome [2]
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Determine incidence of Treatment Emergent Adverse Events
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Assessment method [2]
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To determine the incidence of Treatment Emergent Adverse Events (TEAEs) including all grades of TEAEs and abnormal laboratory finding AEs
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Timepoint [2]
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12 months
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Secondary outcome [1]
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Objective Response Rate (ORR)
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Assessment method [1]
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To assess the Objective Response Rate (ORR) includes partial response (PR) and complete response (CR) of injected tumours as well as non-injected tumours.
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Timepoint [1]
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24 months
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Secondary outcome [2]
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Best Overall Response (BOR)
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Assessment method [2]
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To assess the Best Overall Response (BOR) of injected as well as non-injected tumours.
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Timepoint [2]
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24 months
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Secondary outcome [3]
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Durable Response Rate (DRR)
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Assessment method [3]
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To assess the Durable Response Rate (DRR) of injected tumours.
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Timepoint [3]
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24 months
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Secondary outcome [4]
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Duration of Response (DoR)
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Assessment method [4]
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To assess the Duration of Response (DoR) of injected tumours
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Timepoint [4]
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24 months
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Secondary outcome [5]
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Progression Free Survival (PFS)
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Assessment method [5]
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To assess the Progression Free Survival (PFS). Defined as the length of time during and after treatment that a patient lives without disease progression.
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Timepoint [5]
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24 months
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Secondary outcome [6]
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Incidence of treatment related and non-treatment related Treatment Emergent Adverse Events (TEAEs) and abnormal laboratory tests.
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Assessment method [6]
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All Grade = 3 TEAEs, serious (including fatal) AEs (SAEs), and TEAEs defined as events of interest by the Investigator.
Grading will be as per 'Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, 2017'. The CTCAE scale is measured from Grade 1 (mild) to Grade 5 (death).
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Timepoint [6]
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24 months
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Eligibility
Key inclusion criteria
A patient will be eligible for study participation if they meet ALL of the following
criteria:
1. Are willing and able to provide written informed consent for the study prior to any
protocol-required procedures and to comply with all local and study requirements.
(Note: If a patient is unable to provide written informed consent, a legally
acceptable representative may provide consent on their behalf).
2. Are an adult at least 18 years of age on the day of providing informed consent.
3. Have a histologically confirmed diagnosis of melanoma that is Stage IIIB to IV M1c
(AJCC 8th Ed.) for whom surgery is not recommended. Only patients previously exposed
to a checkpoint inhibitor are eligible. Prior BRAF inhibitor therapy is allowed for
BRAF V600+ patients.
4. Have measurable disease per RECIST v1.1 including cutaneous or subcutaneous tumours,
or regional lymph nodes consisting of = 1 target tumour accessible and amenable to
intratumoural injection and = 1 target tumour designated as a non-injected tumour for
observation that can be accurately measured by contrast enhanced CT or MRI as assessed
by the Investigator's local site radiology.
5. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6. Have life expectancy of more than 12 weeks.
7. Have adequate organ function as defined below. Specimens must be collected within 10
days prior to the start of study treatment.
Haematological:
Absolute neutrophil count (ANC) = 1500/µL Platelets = 100 000/µL Haemoglobin = 9.0
g/dL OR = 5.6 mmol/L1
Renal
Creatinine OR Measured or calculated2 creatinine clearance (GFR can also be used in
place of creatinine or CrCl) = 1.5 × ULN OR
= 30 mL/min for patient with creatinine levels > 1.5 × institutional ULN
Hepatic
Total bilirubin: = 1.5 × ULN OR direct bilirubin = ULN for patients with total
bilirubin levels > 1.5 × ULN
AST (SGOT) and ALT (SGPT) = 2.5 × ULN (= 5 × ULN for patients with liver metastases)
Coagulation
International normalized ratio (INR) OR prothrombin time (PT) Activated partial
thromboplastin time (aPTT): = 1.5 × ULN unless patient is receiving anticoagulant
therapy as long as PT or aPTT is within therapeutic range of intended use of
anticoagulants
8. Meet the following conditions:
1. A male patient must agree to use adequate contraception (as defined below) from
the first day of Screening prior to study entry, for the duration of study
participation, and for at least 90 days (one spermatogenesis cycle) following
their last treatment day. Additionally, male patients must agree to not donate
sperm or father children for the duration of study participation and for at least
90 days following their last treatment day.
2. A female patient is eligible to participate if she is not pregnant (as
demonstrated by negative serum beta-human chorionic gonadotropin [ßhCG] pregnancy
test), not breastfeeding, agrees to not conceive children for at least 120 days
following their last study treatment day, and at least one of the following
conditions applies:
i) Not a woman of childbearing potential (WOCBP) (i.e., pre-menarchal, surgically
permanently sterile [hysterectomy, bilateral salpingectomy and bilateral oophorectomy]
or = 12 months post-menopausal without an alternative medical cause), or
ii) A WOCBP (i.e., not pre-menarchal, not surgically permanently sterile [hysterectomy,
bilateral salpingectomy and bilateral oophorectomy] or not = 12 months post-menopausal
without an alternative medical cause), who agrees to use adequate contraception (as defined
below) from the first day of Screening prior to study entry, for the duration of study
participation and for at least 120 days following their last study treatment day.
c. Adequate contraception includes sexual abstinence (only if preferred method of birth
control); oral, intravaginal or transdermal combined estrogen and progesterone hormonal
contraception associated with inhibition of ovulation; oral, injectable or implantable
progesterone-only hormonal contraception associated with inhibition of ovulation;
intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal
occlusion; or only vasectomized sexual partner(s).
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
A patient will be excluded from study participation if ANY of the following criteria apply:
1. Patients who are planning to receive intratumoural treatment or radiotherapy to any of
the intended target tumours within 4 weeks prior to Screening, or during treatment
with tigilanol tiglate or pembrolizumab, or who have received radiotherapy within 2
weeks of the start of study treatment. (Note: Patients must have recovered from all
radiation-related toxicities, not require corticosteroids, and not have had radiation
pneumonitis. A 4-week washout is permitted for palliative radiation [=4 weeks of
radiotherapy] to non-CNS disease).
2. A tumour intended for injection that is immediately adjacent to, or with infiltration
into, any major artery or vein.
3. A tumour intended for injection located in an area where post-injection swelling could
compromise the airway.
4. Any previous intervention in the area of the intended injected tumour in proximity of
the airway (such that tracking of the injected fluid may be unpredictable and could
lead to airway swelling).
5. A histologically confirmed diagnosis of uveal or mucosal melanoma as the only intended
injected tumour.
6. Have a positive urine pregnancy test within 72 hours prior to start of study treatment
(Note: If the urine test is positive or cannot be confirmed as negative, a serum
pregnancy test will be required).
7. Have received a live vaccine within 30 days prior to the start of study treatment.
Examples of live vaccines include, but are not limited to, the following: measles,
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
Calmette-Guérin (BCG) and typhoid vaccine. (Note: Seasonal influenza vaccines for
injection are generally killed virus vaccines and are allowed; however, intranasal
influenza vaccines [e.g., FluMist®] are live attenuated vaccines and are not allowed).
8. Are planning to receive concomitant other biologic therapy, hormonal therapy, other
chemotherapy to treat their melanoma while on study treatment.
9. Have received any of the following within 4 weeks prior to the start of study
treatment; systemic anticancer therapy, including investigational agents, or has
participated in a study of an investigational agent or has used an investigational
device. (Note: Patients who have entered the follow-up phase of an investigational
study may participate as long as it has been at least 4 weeks after the last dose of
the previous investigational agent). Patients must have recovered from all AEs due to
previous therapies to = Grade 1 or baseline patients with = Grade 2 neuropathy may be
eligible. (Note: If patient received major surgery, they must have recovered
adequately from the toxicity and/or complications from the intervention prior to
starting study treatment). (Note: Patients who have received systemic anticancer
therapy can be considered for inclusion provided a washout period of 4 weeks or 5
half-lives, whichever is shorter, has occurred).
10. Have known, current or history of central nervous system metastases, active cerebral
metastasis and/or carcinomatous meningitis.
11. Have any bleeding diathesis or coagulopathy, or are taking warfarin, that would make
intratumoural injection or biopsy unsafe.
12. Clinically significant acute or unstable cardiovascular, cerebrovascular disorders.
13. Patients with significant peripheral vascular disease whose accessible tumours
intended for injection are located in their extremities.
14. Have prior allogeneic tissue/solid organ transplant.
15. Have a history of allergic reactions or severe hypersensitivity (Grade = 3) attributed
to tigilanol tiglate or pembrolizumab, compounds of similar chemical or biologic
composition to tigilanol tiglate or pembrolizumab, any of their excipients or other
agents used in the study, or have experienced unacceptable toxicity to a checkpoint
inhibitor.
16. Have an active infection requiring systemic therapy.
17. Have known immunodeficiency or are receiving chronic systemic steroid therapy (in
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 7 days prior to the start of study treatment.
18. Have a known additional malignancy that is progressing or has required active
treatment within the past 3 years. (Note: Patients with basal cell carcinoma of the
skin, squamous cell carcinoma of the skin, or carcinoma in situ [e.g., breast
carcinoma, or cervical cancer in situ] that have undergone potentially curative
therapy are not excluded).
19. Have active autoimmune disease that has required systemic treatment in the past 2
years (i.e., with use of disease modifying agents, corticosteroids or
immunosuppressive drugs). (Note: Replacement therapy [e.g., thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency]
is not considered a form of systemic autoimmune treatment and is allowed).
20. Have a history of non-infectious pneumonitis / interstitial lung disease that required
steroids or has current pneumonitis / interstitial lung disease.
21. Have known human immunodeficiency virus (HIV) and/or history of Hepatitis B or
Hepatitis C viral infections, or known to be positive for Hepatitis B antigen (HbsAg),
Hepatitis B virus (HBV) DNA or Hepatitis C Antibody or RNA. (Note: Active Hepatitis C
virus [HCV] is defined by a known positive Hepatitis C Antibody result and known
quantitative HCV RNA results greater than the lower limits of detection of the assay).
22. Have a known psychiatric or substance abuse disorder that would interfere with the
patient's ability to cooperate with the requirements of the study.
23. Have a history of or current evidence of any condition, therapy or laboratory
abnormality that might confound the results of the study, interfere with the patient's
participation for the full duration of the study, or is not in the best interest of
the patient to participate, in the opinion of the treating Investigator.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
N/A
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Single group
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Other design features
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Phase
Phase 1/Phase 2
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Terminated
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
7/05/2021
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
12/07/2022
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Sample size
Target
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Accrual to date
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Final
3
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Recruitment in Australia
Recruitment state(s)
NSW,QLD
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Recruitment hospital [1]
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Melanoma Institute Australia - Wollstonecraft
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Recruitment hospital [2]
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Cairns and Hinterland Hospital and Health Service - Cairns
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Recruitment postcode(s) [1]
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2065 - Wollstonecraft
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Recruitment postcode(s) [2]
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4870 - Cairns
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
QBiotics Group Limited
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Address
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Country
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Other collaborator category [1]
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Commercial sector/Industry
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Name [1]
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Merck Sharp & Dohme LLC
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Address [1]
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Country [1]
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Ethics approval
Ethics application status
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Summary
Brief summary
A Phase Ib/IIa, multicentre, open label, dose-escalation study to evaluate the safety,
tolerability, and preliminary effectiveness of intratumoural tigilanol tiglate in combination
with intravenous pembrolizumab in adult patients with unresectable, Stage IIIB to IV M1c
melanoma.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT04834973
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Prof. Georgina Long, BSc PhD MBBS FRACP FAHMS
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Address
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Melanoma Institute Australia
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Country
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Address
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Country
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Phone
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Fax
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Email
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT04834973
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