Trial registered on ANZCTR


Trial ID
ACTRN12618000003279
Ethics application status
Approved
Date submitted
8/12/2017
Date registered
9/01/2018
Date last updated
9/01/2018
Type of registration
Retrospectively registered

Titles & IDs
Public title
An Open-Label Trial to Investigate the Safety, Tolerability, Pharmacokinetics, Biological, and Clinical Activity of AGEN1884 in Combination with AGEN2034 in Patients with Metastatic or Locally Advanced Solid Tumours
Scientific title
C-550-01 A Phase 1/2, Open-Label, Multi-Arm Trial to Investigate the Safety, Tolerability, Pharmacokinetics, Biological, and Clinical Activity of AGEN1884 in Combination with AGEN2034 in Subjects with Metastatic or Locally Advanced Solid Tumours, and Expansion into Select Solid Tumours
Secondary ID [1] 293543 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Advanced or Metastatic Solid Tumour Cancer 305758 0
Condition category
Condition code
Cancer 304971 304971 0 0
Malignant melanoma
Cancer 304972 304972 0 0
Lung - Non small cell
Cancer 304973 304973 0 0
Cervical (cervix)
Cancer 304974 304974 0 0
Kidney
Cancer 304975 304975 0 0
Bladder
Cancer 304976 304976 0 0
Bowel - Back passage (rectum) or large bowel (colon)
Cancer 304977 304977 0 0
Brain
Cancer 304978 304978 0 0
Prostate
Cancer 304979 304979 0 0
Hodgkin's
Cancer 304980 304980 0 0
Other cancer types

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
In Phase 1 of the study approximately 20 eligible patients with advanced or metastatic tumours will be enrolled. An initial 3 eligible patients will be enrolled to the starting dose group CDL1 per below:
CDL1 - AGEN1884 1 mg/kg every 6 weeks + AGEN2034 1 mg/kg every 2 weeks
After 21 days a safety review will be completed and a decision will be made on the dose level for Cohort 2 to start enrolment, this dose will be either:
CDL-1 - AGEN1884 0.3 mg/kg every 6 weeks + AGEN2034 1 mg/kg every 2 weeks (potential de-escalation CDL)
CDL2 - AGEN1884 1 mg/kg every 6 weeks + AGEN2034 3 mg/kg every 2 weeks (maximum planned CDL)
Participants will only be recruited into 1 cohort of the study and 1 phase of the study.

AGEN2034 and AGEN1884 will be administered as an intravenous infusion in clinic at the study site under the review of study doctors and nurses to ensure this is correctly administered and to review for any adverse reaction. When administered together AGEN2034 is infused first followed by AGEN1884 on the same day.
Each patient will receive the combination treatment for a maximum of 24 months or until confirmed disease progression, unacceptable toxicity, or any criterion for withdrawal from the trial or the investigational medicinal products (IMPs) occur.
In Phase 2 approximately 41 patients will be enrolled to the study who have recurrent, unresectable, or metastatic cervical cancer
In Phase 2, the selected CDL of AGEN2034 and AGEN1884, established in Phase 1, will be administered for a maximum of 2 years or until confirmed progression, unacceptable toxicity, or any criterion for stopping the study drugs or withdrawal from the trial occurs.
Intervention code [1] 299784 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 304144 0
Phase 1: To assess the safety and tolerability of AGEN1884 in combination with AGEN2034 in subjects with metastatic and/or locally advanced solid tumors. This will be assessed on review of the dose-limiting toxicity events in participants in dose escalation during the first 21 days of treatment.
Timepoint [1] 304144 0
Phase 1: Occurrence of dose-limiting toxicity in subjects in dose escalation during the first 21 days of treatment.
Primary outcome [2] 304145 0
Phase 2: To assess the best overall response (BOR), as determined by the Independent Endpoint Review Committee (IERC), according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).
Timepoint [2] 304145 0
Phase 2: Confirmed BOR per RECIST 1.1, as determined by the IERC, in the analysis population at end of study for all participants up to 24 months following treatment initiation.
Secondary outcome [1] 341094 0
To assess and progression-free survival (PFS) per RECIST 1.1.
Timepoint [1] 341094 0
PFS per RECIST 1.1, as determined by investigator, in the analysis population, from commencement of treatment and up at end of study, up to 24 months following initial treatment.
Secondary outcome [2] 341478 0
To assess duration of response (DOR) to treatment per RECIST 1.1
Timepoint [2] 341478 0
DOR per RECIST 1.1, as determined by investigator, in the analysis population, from commencement of treatment and up at end of study, up to 24 months following initial treatment.

Eligibility
Key inclusion criteria
1. Voluntarily agree to participate by giving written informed consent. Participation in pharmacogenomics testing is optional.
2. Be greater than or equal to 18 years of age.
3. Diagnosis:
a. Phase 1 – Part A: Have a histologically or cytologically confirmed diagnosis of a metastatic or locally advanced solid tumor for which no standard therapy is available or standard therapy has failed.
b. Phase 2 - Part B: Have a histologically or cytologically confirmed diagnosis of metastatic or locally advanced, unresectable squamous-cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix; and have relapsed after a platinum-containing doublet administered for treatment of advanced (recurrent, unresectable, or metastatic) disease.
Note: The following cervical tumors are not eligible: minimal deviation/adenoma malignum, gastric type adenocarcinoma, clear cell carcinoma, and mesonephric carcinoma. Histologic confirmation of the original primary tumor is required via pathology report.
Note: Chemotherapy administered concurrently with primary radiation (e.g., weekly cisplatin) is not counted as a systemic chemotherapy regimen unless subject progressed within 6 months of treatment completion.
Note: Adjuvant chemotherapy given following completion of radiation therapy (or concurrent chemotherapy and radiation therapy) is not counted as a systemic chemotherapy regimen (e.g., paclitaxel and carboplatin for = 4 cycles) unless subject progressed within 6 months of completing adjuvant therapy.
Note: Subjects who have not received a platinum-containing doublet administered for treatment of their advanced (recurrent, unresectable, or metastatic) disease are not eligible.
Note: Subjects who have received more than 1 prior systemic treatment regimen for advanced or metastatic disease are not eligible.
4. Measurable Disease
a. Phase 1 – Part A: Have objective evidence of disease; the presence of measurable disease is not required.
b. Phase 2 – Part B: Have measurable disease on imaging based on RECIST version 1.1.
Note: Subjects must have at least one "target lesion" to be used to assess response, as defined by RECIST version 1.1. Tumors within a previously irradiated field will be designated as "non-target" lesions unless progression is documented or a biopsy is obtained to confirm persistence at least 90 days following completion of radiation therapy.
5. Have a life expectancy of at least 3 months and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6. Have adequate organ function as indicated by the following laboratory values:
a. Adequate hematological function defined by absolute neutrophil count (ANC) greater than 1.5 x 109/L, platelet count greater than 100 x 109/L, and hemoglobin greater than 9 g/dL (without transfusions within 1 week of first dose).
b. Adequate hepatic function based by a total bilirubin level less than the institutional upper limit of normal (IULN), aspartate aminotransferase (AST) level less than 2.5 times IULN, alanine aminotransferase (ALT) level less than 2.5 times IULN, and alkaline phosphatase is equal to 2.5 IULN.
c. Adequate renal function defined as Creatinine equals 1.5 times IULN OR calculated creatinine clearance greater than 60 mL/min for subjects with creatinine levels greater than 1.5 times IULN (If no local guideline is available, creatinine clearance should be calculated using the Cockcroft-Gault Method).
d. Adequate coagulation defined by international normalized ratio (INR) or prothrombin time equal to 1.5 times IULN (unless the subject is receiving anticoagulant therapy); and activated partial thromboplastin time (aPTT) equal to 1.5 times IULN (unless the subject is receiving anticoagulant therapy)
7. Have no history of prior malignancy, with the exception of basal cell carcinoma of the skin, superficial bladder cancer, squamous-cell carcinoma of the skin, in situ cervical cancer, or has undergone potentially curative therapy with no evidence of that disease recurrence for 5 years since initiation of that therapy.
Note: In Phase 2, the history and time requirement for no evidence of disease for 5 years does not apply to the cancer for which the subject is enrolled in the study.
8. In Phase 2, subjects must have provided sufficient and adequate formalin fixed tumor tissue sample preferably from a biopsy of a tumor lesion either at the time of or after the diagnosis of advanced or metastatic disease has been made AND from a site not previously irradiated.
Note: Needle or excisional biopsies, or resected tissue is required
9. Female subjects must have a negative serum pregnancy test at screening (within 72 hours of first dose of study medication) if of childbearing potential or be of non-child bearing potential. Non-childbearing potential is defined as (by other than medical reasons):
a. is equal to 45 years of age and has not had menses for greater than 1 year,
b. Amenorrheic for less than 2 years without a hysterectomy and oophorectomy and a follicle-stimulating hormone (FSH) value in the postmenopausal range upon pretrial (screening) evaluation,
c. Whose status is post hysterectomy, oophorectomy or tubal ligation.
10. If of childbearing potential, female subjects must be willing to use two adequate barrier methods throughout the study, starting with the screening visit through 120 days after the last dose of study treatment.
Note: Abstinence is acceptable if this is the established and preferred contraception for the subject.
11. Male subjects with a female partner(s) of child-bearing potential must agree to use two adequate barrier methods throughout the trial starting with the screening visit through 120 days after the last dose of study treatment is received. Males with pregnant partners must agree to use a condom; no additional method of contraception is required for the pregnant partner.
Note: Abstinence is acceptable if this is the established and preferred contraception for the subject.
12. Is willing and able to comply with the requirements of the protocol.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
The subject must be excluded from participating in the trial if the subject:
1. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigation device within 4 weeks of the first dose of treatment.
2. Has received prior systemic cytotoxic chemotherapy, biological therapy, radiation therapy, OR major surgery within 3 weeks or 5 half-lives (whichever is longer) of the first dose of trial treatment.
3. Has received prior therapy with any antibody/drug targeting T-cell co-regulatory proteins (immune checkpoints) such as anti–PD-1, anti–PD-L1, or anti–cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibodies.
Note: In Phase 1, prior treatment with a CTLA-4 antibody is permissible for subjects with metastatic melanoma.
4. Has persisting toxicity related to prior therapy of National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 (NCI-CTCAE) greater than Grade 1 severity.
Note: Sensory neuropathy of equal to Grade 2 is acceptable.
5. Is expected to require any other form of systemic or localized antineoplastic therapy while on trial (including maintenance therapy with another agent, radiation therapy, and/or surgical resection).
6. Has known severe hypersensitivity reactions to monoclonal antibodies (NCI-CTCAE Grade is equal to 3), any history of anaphylaxis, or uncontrolled asthma (i.e., is equal to 3 features of partly controlled asthma).
7. Is receiving systemic corticosteroid therapy equal to 3 days prior to the first dose of trial treatment or receiving any other form of systemic immunosuppressive medication (corticosteroid use on study for management of immune-related adverse events, and/or a premedication for IV contrast allergies/reactions is allowed). Subjects who are receiving daily corticosteroid replacement therapy are an exception to this rule. Daily prednisone at doses of 5-7.5 mg or equivalent hydrocortisone dose are examples of permitted replacement therapy.
8. Has a central nervous system (CNS) tumor, metastasis(es), and/or carcinomatous meningitis identified either on the baseline brain imaging obtained during the screening period OR identified prior to consent.
Note: Subjects with history of brain metastases that have been treated may participate provided they show no evidence of intracranial disease at screening (defined as 2 brain images, both of which are obtained after treatment to the brain metastases. These imaging scans should both be obtained at least four weeks apart and show no evidence of intracranial disease). In addition, any neurologic symptoms that developed either as a result of the brain metastases or their treatment must have returned to baseline or resolved. Any steroids administered as part of this therapy must be completed at least three days prior to study medication.
9. Has active or history of autoimmune disease that has required systemic treatment within 2 years of the start of trial treatment (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (i.e., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
Note: Subjects with diabetes type 1, vitiligo, psoriasis, hypo-, or hyperthyroid disease not requiring immunosuppressive treatment are eligible.
10. Has had an allogeneic tissue/solid organ transplant.
11. Has or had interstitial lung disease (ILD) OR has had a history of pneumonitis that has required oral or IV corticosteroids.
12. Has an active infection requiring intravenous systemic therapy.
13. Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
14. Has known active Hepatitis B, Hepatitis C or tuberculosis. Active Hepatitis B is defined as a known positive HBsAg result. Active Hepatitis C is defined by a known positive Hep C Ab result and known quantitative HCV RNA results greater than the lower limits of detection of the assay.
15. Has clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke or myocardial infarction within 6 months of enrollment, unstable angina, congestive heart failure (New York Heart Association class is equal to II), or serious uncontrolled cardiac arrhythmia requiring medication.
16. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator.
17. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
18. Is, at the time of signing informed consent, a regular user (including “recreational use”) of any illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol).
19. Is legally incapacitated or has limited legal capacity.
20. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of AGEN2034 and/or AGEN1884.

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
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
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)
NSW,QLD,WA

Funding & Sponsors
Funding source category [1] 298157 0
Commercial sector/Industry
Name [1] 298157 0
Agenus Inc
Address [1] 298157 0
3 Forbes Road, Lexington MA 02421
Country [1] 298157 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Clinical Network Services
Address
Level 4, 88 Jephson Street, Toowong QLD 4066
Country
Australia
Secondary sponsor category [1] 297247 0
None
Name [1] 297247 0
Address [1] 297247 0
Country [1] 297247 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299172 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 299172 0
129 Glen Osmond Road Eastwood South Australia 5063
Ethics committee country [1] 299172 0
Australia
Date submitted for ethics approval [1] 299172 0
18/10/2017
Approval date [1] 299172 0
20/11/2017
Ethics approval number [1] 299172 0
2017-10-766

Summary
Brief summary
This study aims to evaluate the effects of AGEN1884 in combination with AGEN2034 on biochemical and physiologic functions in Patients with Advanced or Metastatic Solid Tumours

Who is it for?
You may be eligible to join this study if you are aged 18 years or above and have a histologically or cytologically confirmed, metastatic or locally advanced solid tumor for which no standard therapy exists or standard therapy has failed.
For Phase 2 of the study you will need to have histologically or cytologically confirmed diagnosis of metastatic or locally advanced, unresectable squamous-cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix; and have relapsed after a platinum-containing doublet administered for treatment of advanced (recurrent, unresectable, or metastatic) disease.

Participants will only participate in one phase of the study.

Study details:
Approximately 20 patients will be enrolled to the Phase 1 and will receive either of the initial starting doses below, depending on the time they are enrolled. The first 3 participants enrolled will receive the starting dose below:
CDL1: AGEN1884 1 mg/kg every 6 weeks + AGEN2034 1 mg/kg every 2 weeks
After 21 days a safety review of the data will determine the next dose level for part 2 of the Phase 1 study which will be either:
CDL2: AGEN1884 1 mg/kg every 6 weeks + AGEN2034 3 mg/kg every 2 weeks
CDL-1: AGEN1884 0.3 mg/kg every 6 weeks + AGEN2034 1 mg/kg every 2 weeks

The 41 patients with cervical cancer in Phase 2 will have their dose decided based on the selected combination dose level (CDL) established in Phase 1.

The maximum trial duration for a patient is estimated to be approximately 49 months. This includes a screening period; a planned treatment period of up to approximately 24 months; and a treatment follow-up period of up to 24 months after the last treatment dose or until disease progression and/or initiation of a new line of therapy.

The investigators seek to identify/confirm the safety, tolerability, biological and clinical activity that correlate with immune activation.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 79538 0
Dr Jermaine Coward
Address 79538 0
Icon Cancer Care South Brisbane
Level 5 Mater Medical Centre
293 Vulture Street
South Brisbane QLD 4101
Country 79538 0
Australia
Phone 79538 0
+61 7 3737 4500
Fax 79538 0
Email 79538 0
Jim.Coward@iconcancercare.com.au
Contact person for public queries
Name 79539 0
Mr Adam Stoneley
Address 79539 0
Icon Cancer Foundation Head Office
Level 1, 22 Cordelia Street
South Brisbane
QLD 4101
Country 79539 0
Australia
Phone 79539 0
+61 7 3737 4558
Fax 79539 0
Email 79539 0
adam.stoneley@iconcf.org.au
Contact person for scientific queries
Name 79540 0
Dr Jermaine Coward
Address 79540 0
Icon Cancer Care South Brisbane
Level 5 Mater Medical Centre
293 Vulture Street
South Brisbane QLD 4101
Country 79540 0
Australia
Phone 79540 0
+61 7 3737 4500
Fax 79540 0
Email 79540 0
Jim.Coward@iconcancercare.com.au