Trial registered on ANZCTR


Trial ID
ACTRN12617001061325
Ethics application status
Approved
Date submitted
4/07/2017
Date registered
20/07/2017
Date last updated
22/08/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Study To assess the safety and tolerability of AGEN1884 administered in combination with pembrolizumab as a first-line treatment of subjects with metastatic Non Small Cell Lung Cancer (NSCLC).
Scientific title
A Phase IIa, Open-Label Trial to Investigate the Safety, Tolerability, Pharmacokinetics, Biological, and Clinical Activity of AGEN1884 in Combination with Pembrolizumab in Subjects with Chemotherapy Naïve, PD-L1 high metastatic Non–Small Cell Lung Cancer (NSCLC)
Secondary ID [1] 292348 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Non Small Cell Lung Cancer 303896 0
Condition category
Condition code
Cancer 303263 303263 0 0
Lung - Non small cell

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Safety Run-In Phase
the first 3 patients enrolled will start on the first dosing level. Participants will receive 1mg/kg of AGEN1884 via intravenous infusion every 6 weeks in combination with Pembrolizumab 200mg via intravenous infusion every 3 weeks for up to 24 months, or until disease progression or discontinuation due to side effects.
If there are too many side effects at the first dose level by day 21, the study will proceed with the second dosing level (Dose Level 2) and another 3 participants will receive 0.3mg/kg of AGEN1884 via intravenous infusion every 6 weeks and Pembrolizumab 200mg via intravenous infusion every 3 weeks for up to 24 months, or until disease progression or discontinuation due to side effects.
Efficacy Phase
Once the first phase (Safety Run-in Phase) of the study is complete and the dose level of AGEN1884 is selected, the study will proceed to the second phase of the study (Efficacy Phase) using the selected dose level in combination with pembrolizumab for up to 24 months, or until disease progression or discontinuation due to side effects.
If Dose Level 2 is found have too many side effects by day 21, further enrolment will be paused in order for Agenus and the study doctors to review the data and decide if the study should continue.
Safety Follow Up
After discontinuing treatment, participants will be followed up for up to a further 12 months.
At each visit the following assessments will be performed;
Physical Examination: to assess general health.
Vital signs: including body temperature, respiratory rate, heart rate and blood pressure.
Performance Status: Assess the impact the cancer has on daily living activities.
Routine blood samples: Up to 7 mL/ 1-2 teaspoons of blood to assess the health of patients liver, kidneys and blood cells.
Tumour Imaging: Tumour imaging by computerised tomography (CT) or magnetic resonance imaging (MRI) at weeks 6, 12 and then every 9 weeks.
Research Blood samples: Up to 45 mL/ 9 teaspoons of blood.

The maximum total study duration is approximately 37 months for each participant.
Intervention code [1] 298525 0
Treatment: Drugs
Comparator / control treatment
No Control Group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 302637 0
Occurrence of Dose Limiting Toxicities in subjects during the first 21 days of treatment in the Safety Run-in Phase of the trial. Dose Limiting Toxicities will be assesed according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (NCI-CTCAE) V4.03.
Timepoint [1] 302637 0
Day 21 of Safety Run-in Phase
Secondary outcome [1] 336607 0
Frequency, severity, and duration of treatment-emergent Adverse Events (TEAEs) for all dose groups according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.03
Timepoint [1] 336607 0
Last Patient Last Visit
Secondary outcome [2] 336608 0
Confirmed Best Overall Response (BOR) per RECIST 1.1, as determined by an Independent Endpoint Review Committee (IERC) and investigator, in the analysis population.
Timepoint [2] 336608 0
End of Study
Secondary outcome [3] 336609 0
Duration of response per RECIST 1.1, as determined by an IERC and investigator, defined as time from first observation of response to first observation of documented disease progression (or death within 12 weeks of last tumor assessment). Subjects without an event at analysis cutoff date will be censored on date of last tumor assessment.
Timepoint [3] 336609 0
End of Study
Secondary outcome [4] 336610 0
Progression Free Survival (PFS) time, defined as time from first treatment administration to first observation of documented disease progression (or death within 12 weeks of last tumor assessment), per RECIST 1.1, as determined by an IERC and investigator. Subjects without an event at analysis cutoff date will be censored on date of last tumor assessment.
Timepoint [4] 336610 0
End of Study
Secondary outcome [5] 336611 0
Overall Survival (OS) time, defined as time from first administration of trial treatment to death. For subjects who are still alive at time of data cutoff for trial analysis or who are lost to follow-up, survival will be censored at the last recorded date that the subject is known to be alive as of the cutoff date for analysis..
Timepoint [5] 336611 0
End of Study
Secondary outcome [6] 336612 0
Unconfirmed response at 12 weeks from first dose per RECIST 1.1 based on investigator assessment...
Timepoint [6] 336612 0
12 weeks fro first drug administration for every participant
Secondary outcome [7] 336613 0
Pharmacokinetic profile of AGEN1884 and pembrolizumab. in combination will be assessed by serum analysis:
-Area under the concentration-time curve from time of dosing to time of last observation (calculated by linear trapezoidal summation).
- Area under the curve from time of dosing extrapolated to infinity (calculated by linear trapezoidal summation and extrapolated to infinity using C last/z).
- Terminal elimination rate constant. Is determined from the slope of the regression line of log (concentration) vs. time with the following constraints: (i) there must be greater than or equal to 3 consecutive measurable concentrations; (ii) all concentrations must be declining with time; and (iii) the correlation coefficient (r) of regression must be greater than or equal to 0.95.
-Cmax: Maximum plasma concentration observed post-dose.
-tmax: Time at which Cmax occurs.
-Elimination half-life, determined as 0.693.
Timepoint [7] 336613 0
Blood samples collected at:
Day 1 of cycles 1 & 2:Before administration of pembrolizumab, before administration of AGEN1884, and 30 (± 15) minutes, 2 hours (± 15 minutes), and 4 hours (± 15 minutes) post-administration of AGEN1884.
Day 2 of cycles 1 & 2: At 24 (± 2) hours post-infusion of AGEN1884.
Day 22 of cylces 1 & 2: Before administration of pembrolizumab, and 30 (± 15) minutes, 2 hours (± 15 minutes), and 4 hours (± 15 minutes) post-administration of pembrolizumab.

Pharmacokinetics will be analysed at the end of the Study.
Secondary outcome [8] 336614 0
Immunogenicity of AGEN1884 and pembrolizumab in combination. Immunigenicity will be assessed by serum analysis. A testing strategy will be implemented and conducted in line with:
-Immunogenicity Assessment of Biotechnology-Derived Therapeutic Proteins (EMEA/CHMP/BMWP/14327/2006) (European Medicines Agency, 2015).
-Immunogenicity Assessment of Monoclonal Antibodies Intended for In Vivo Clinical Use (EMEA/CHMP/BMWP/86289/2010) (European Medicines Agency, 2012).
-FDA (2009, draft) Guidance for Industry: Assay Development for Immunogenicity Testing of Therapeutic Proteins (US Food and Drug Administration, 2016).
A qualified method that uses an acid dissociation step to detect ADAs in the presence of excess drug in human serum will be applied. Removal of drug after acid treatment is not required. ADA titers of positive samples will be determined.
Timepoint [8] 336614 0
Blood samples collected at:
Day 1 of cycles 1 & 2:Before administration of pembrolizumab, before administration of AGEN1884, and 30 (± 15) minutes, 2 hours (± 15 minutes), and 4 hours (± 15 minutes) post-administration of AGEN1884.
Day 2 of cycles 1 & 2: At 24 (± 2) hours post-infusion of AGEN1884.
Day 22 of cylces 1 & 2: Before administration of pembrolizumab, and 30 (± 15) minutes, 2 hours (± 15 minutes), and 4 hours (± 15 minutes) post-administration of pembrolizumab.

Immunogenicity will be analysed at the end of the Study.

Eligibility
Key inclusion criteria
In order to be eligible for participation in this trial the subject must:
1. Voluntarily agree to participate by giving written informed consent. The participation in the pharmacogenomics testing is optional.
2. Be greater than or equal to 18 years of age.
3. Have a histologically or cytologically confirmed diagnosis of NSCLC, is stage IV, does not have an EGFR sensitizing (activating) mutation or ALK translocation, and has not received prior systemic chemotherapy treatment for their metastatic NSCLC.
4. Have measurable disease based on RECIST 1.1 as determined by the site.
5. Have a life expectancy of at least 3 months and a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Status
6. Have adequate organ function as indicated by the following laboratory values:
a. Adequate hematological function defined by absolute neutrophil count (ANC) greater than or equal to 1.5 x 109/L, platelet count greater than or equal to 100 x 109/L, and hemoglobin greater than or equal to 9 g/dL (without transfusions within 2 weeks of first dose).
b. Adequate hepatic function based by a total bilirubin level less than or equal to the institutional upper limit of normal (IULN), aspartate aminotransferase (AST) level less than or equal to 1.5 x IULN, alanine aminotransferase (ALT) level less than or equal to 1.5 x IULN, and alkaline phosphatase less than or equal to 2.5 ULN.
c. Adequate renal function defined as Creatinine less than or equal to 1.5 x IULN OR calculated creatinine clearance greater than 60 mL/min for subjects with creatinine levels greater than 1.5 x 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 less than or equal to 1.5 x IULN (unless the subject is receiving anticoagulant therapy); and activated partial thromboplastin time (aPTT) less than or equal to 1.5 x IULN (unless the subject is receiving anticoagulant therapy)
e. Adequate endocrine function defined by thyroid stimulating hormone (TSH) within normal limits. Note: if TSH is not within normal limits at baseline, the subject may still be eligible if T3 and free T4 are within normal limits.
7. Subject has 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.
8. Have provided a formalin fixed tumor tissue sample from a biopsy of a tumor lesion either at the time of or after the diagnosis of metastatic disease has been made AND from a site not previously irradiated to assess for PD-L1 status.
Biopsies obtained PRIOR to the administration of any systemic therapy for the treatment of a subject’s tumor (such as neoadjuvant/adjuvant therapy) will not be permitted for analysis.
The tissue sample must be analyzed by the pathologist (site pathologist or Central Lab), using an FDA approved test.
Fine needle aspirates, endobronchial ultrasound (EBUS) or cell blocks are not acceptable.
Needle or excisional biopsies, or resected tissue is required
9. The subject’s tumor does not harbor an EGFR sensitizing (activating) mutation or ALK translocation.
EGFR sensitizing mutations are those mutations that are amenable to treatment with tyrosine kinase inhibitors including erlotinib, gefitinib, or afatanib. Investigators must be able to produce the source documentation of the EGFR mutation and ALK translocation status in all subjects with non-squamous histologies AND for subjects in whom testing is clinically recommended.
If either an EGFR sensitizing mutation or ALK translocation is detected, additional information regarding the mutation status of the other molecule is not required. If unable to test for these molecular changes, formalin fixed paraffin embedded tumor tissue of any age should be submitted to a central laboratory designated by the sponsor for such testing.
For subjects enrolled who are known to have a tumor of predominantly squamous histology, molecular testing for EGFR and ALK translocation will not be required as this is not standard of care and is not part of current diagnostic guidelines.
10. The subject’s tumor must have high PD-L1 expression (TPS greater than or equal to 50%) as determined by an FDA-approved test.
11. 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):
Greater than or equal to 45 years of age and has not had menses for greater than 1 year,
Amenorrheic for less than 2 years without a hysterectomy and oophorectomy and an follicle-stimulating hormone (FSH) value in the postmenopausal range upon pretrial (screening) evaluation,
Whose status is post hysterectomy, oophorectomy or tubal ligation.
12. 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 therapy.
Note: Abstinence is acceptable if this is the established and preferred contraception for the subject.
13. 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 pembrolizumab 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.
14. Subject 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
Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Has an EGFR sensitizing mutation and/or an ALK translocation.
2. Has received systemic therapy for the treatment of their stage IV NSCLC. Completion of treatment with chemotherapy and/or radiation as part of neoadjuvant/adjuvant therapy is allowed as long as therapy was completed at least 6 months prior to the diagnosis of metastatic disease.
3. 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.
4. Is receiving systemic steroid therapy less than 3 days prior to the first dose of trial treatment or receiving any other form of immunosuppressive medication (corticosteroid use on study for management of ECIs, and/or a premedication for IV contrast allergies/reactions is allowed). Subjects who are receiving daily steroid 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.
5. Is expected to require any other form of systemic or localized antineoplastic therapy while on trial (including maintenance therapy with another agent for NSCLC, radiation therapy, and/or surgical resection)
6. Has received prior systemic cytotoxic chemotherapy, biological therapy, OR major surgery within 3 weeks of the first dose of trial treatment; received thoracic radiation therapy of greater than 30 Gy within 6 months of the first dose of trial treatment.
7. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
8. Has central nervous system (CNS) metastases and/or carcinomatous meningitis identified either on the baseline brain imaging obtained during the screening period OR identified prior to signing the ICF.
9. Active autoimmune disease that has required systemic treatment in past 2 years (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.
10. Has had an allogeneic tissue/solid organ transplant.
11. Has interstitial lung disease (ILD) OR has had a history of pneumonitis that has required oral or IV steroids.
12. Has received or will receive a live vaccine within 30 days prior to the first administration of study medication. Seasonal flu vaccines that do not contain a live virus are permitted
13. Has an active infection requiring intravenous systemic therapy.
14. Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
15. 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.
16. 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 greater than or equal to II), or serious uncontrolled cardiac arrhythmia requiring medication.
17. 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.
18. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
19. 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).
20. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit (Visit 1) through 120 days after the last dose of pembrolizumab 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)
Allocation is not concealed
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
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
The total sample size is expected to be approximately 20 to 26 treated subjects.
The Safety Run-in Phase will consist of approximately 6 to 12 subjects and the Efficacy Phase will consist of approximately 14 which will enable assessment of overall response rate (ORR) in this analysis set.
There is no formal statistical hypothesis that supports determination of this sample size. If 14 responders are observed within N=20 subjects, then the study provides 95% assurance (or confidence) that the true objective response rate of the study therapy will be at least 46%.
For all analyses, descriptive statistics and graphical representation of data will be presented by dose level in the Safety Run-in and Efficacy Phases.
Statistics for continuous variables may include means, medians, ranges, and appropriate measures of variability. Qualitative variables will be summarized by counts and percentages. Uncertainty of estimates will be assessed by confidence intervals. Descriptive statistics will be examined for indications of dose-related toxicity.

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,VIC
Recruitment hospital [1] 8476 0
Scientia Clinical Research - Randwick
Recruitment hospital [2] 8477 0
Icon Cancer Care South Brisbane - South Brisbane
Recruitment hospital [3] 8478 0
Mater Adult Hospital - South Brisbane
Recruitment postcode(s) [1] 16560 0
2031 - Randwick
Recruitment postcode(s) [2] 16561 0
4101 - South Brisbane
Recruitment outside Australia
Country [1] 9038 0
New Zealand
State/province [1] 9038 0
Auckland

Funding & Sponsors
Funding source category [1] 296905 0
Commercial sector/Industry
Name [1] 296905 0
Agenus Inc.
Address [1] 296905 0
3 Forbes Road
Lexington, MA 02421,
U.S.A.
Country [1] 296905 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Agenus Inc.
Address
3 Forbes Road
Lexington, MA 02421,
U.S.A.
Country
United States of America
Secondary sponsor category [1] 295911 0
None
Name [1] 295911 0
None
Address [1] 295911 0
None
Country [1] 295911 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298115 0
Bellberry Limited
Ethics committee address [1] 298115 0
129 Glen Osmond Road
Eastwood South Australia 5063
Ethics committee country [1] 298115 0
Australia
Date submitted for ethics approval [1] 298115 0
21/06/2017
Approval date [1] 298115 0
24/07/2017
Ethics approval number [1] 298115 0
2017-06-406

Summary
Brief summary
The purpose of this study is to assess safety and tolerability, pharmacokinetics and general activity of AGEN1884 in combination with Pembrolizumab in patients with metastatic non-small cell lung cancer (NSCLC).

Who is it for?
You may be eligible to join this study if you are aged 18 years or above, and have a confirmed diagnosis of stage IV non-small cell lung cancer (NSCLC) for which you have not received prior systemic chemotherapy treatment.

Study details
Up to 26 participants will be enrolled over 2 possible dosing levels of AGEN1884 (1 mg/Kg or 0.3 mg/kg) in combination with standard pembrolizumab treatment over two study phases. The first phase of this study (Safety Run-in Phase) will evaluate which dose level to use for the second phase (Efficacy Phase). Pembrolizumab is already approved in Australia and will be administered every 3 weeks by intravenous infusion. . AGEN1884 is not yet approved, and will be administered every 6 weeks by intravenous infusion. Treatment will continue for up to 24 months, or until disease progression or discontinuation due to side effects.

All participants will be monitored regularly for adverse events and treatment response. This will involve physical examination, imaging, and collection of blood samples.

Advances in understanding of immuno-oncology have shown that a ’tumours’ ability to evade the immune system can determine how well one controls and eradicates tumours.There is some evidence that the proposed regimen for this research study is more effective and may have a better safety profile than other combination regimens. Information from this study may help develop new treatments for NSCLC in the future.
Trial website
Nil
Trial related presentations / publications
Nil
Public notes

Contacts
Principal investigator
Name 76042 0
Dr Charlotte Lemech
Address 76042 0
Scientia Clinical Research
5th Floor, Bright Building
Corner High and Avoca Street
Randwick NSW 2031
Australia
Country 76042 0
Australia
Phone 76042 0
+61-2-9382 5807
Fax 76042 0
Email 76042 0
charlotte.lemech@scientiaclinicalresearch.com.au
Contact person for public queries
Name 76043 0
Dr Charlotte Lemech
Address 76043 0
Scientia Clinical Research
5th Floor, Bright Building
Corner High and Avoca Street
Randwick NSW 2031
Australia
Country 76043 0
Australia
Phone 76043 0
+61-2-9382 5807
Fax 76043 0
Email 76043 0
charlotte.lemech@scientiaclinicalresearch.com.au
Contact person for scientific queries
Name 76044 0
Dr Charlotte Lemech
Address 76044 0
Scientia Clinical Research
5th Floor, Bright Building
Corner High and Avoca Street
Randwick NSW 2031
Australia
Country 76044 0
Australia
Phone 76044 0
+61-2-9382 5807
Fax 76044 0
Email 76044 0
charlotte.lemech@scientiaclinicalresearch.com.au