| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic or Locally Advanced Solid Tumors and Cervical Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer that develops in a woman's cervix |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10008231 |
| E.1.2 | Term | Cervical cancer recurrent |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase 1
- To assess the safety and tolerability of AGEN2034 in subjects with metastatic and/or locally advanced solid tumors
Phase 2
- To assess objective response rate (ORR) according to RECIST 1.1 as determined by an Independent Endpoint Review
Committee (IERC) |
|
| E.2.2 | Secondary objectives of the trial |
Phase 1
• To characterize the AGEN2034 pharmacokinetic (PK) profile.
• To correlate AGEN2034 exposure with target occupancy
• To evaluate the immunogenicity of AGEN2034 and to correlate it to exposure
Phase 2
• To assess the safety and tolerability of AGEN2034 in subjects with metastatic and/or locally advanced solid tumors
• To characterize the AGEN2034 PK profile
• To evaluate the immunogenicity of AGEN2034 and correlate it to exposure
• To assess objective response rate (ORR) according to RECIST 1.1 as determined by investigator
• To assess duration of response (DOR), disease control rate (DCR), duration of
stable disease (SD), time to response, and progression-free survival (PFS) time per RECIST 1.1
• To assess overall survival (OS) rate
• To assess OS time
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Voluntarily agree to participate by giving written informed consent. Participation in
pharmacogenomics testing is optional.
2. Be ≥ 18 years of age.
3. Diagnosis and prior systemic treatment:
a. Phase 1: 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:
I. Have (1) a histologically or cytologically confirmed diagnosis of squamous-cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix, and (2) metastatic, locally advanced, and/or unresectable disease at the time of enrollment. Histologic confirmation of the original primary tumor is required via pathology report.
Note: The following cervical tumors are not eligible: minimal deviation/adenoma malignum, gastric type adenocarcinoma, clear cell carcinoma, and mesonephric carcinoma.
II. Has cervical cancer and has relapsed after a platinum-based treatment (first line) regimen for advanced (recurrent, unresectable, or metastatic) disease; Note: Subject receiving chemotherapy concurrently with primary radiation (e.g.,
weekly cisplatin) or subject receiving adjuvant chemotherapy following completion of radiation therapy (e.g., paclitaxel and carboplatin for ≤ 4 cycles) and progressed within 6 months after treatment completion will be eligible as this systemic therapy will be considered as first line treatment.
4. Measurable disease – based on investigator assessment
a. Phase 1: Have objective evidence of disease; the presence of measurable disease is not required.
b. Phase 2: 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) ≥ 1.5 x 109/L, platelet count ≥ 100 x 109/L, and stable hemoglobin ≥ 8 g/dL (without transfusions within 1 week before first dose).
b. Adequate hepatic function based by a total bilirubin level ≤ 1.5 x the institutional upper limit of normal (IULN), aspartate aminotransferase (AST) level ≤ 2.5 x IULN, alanine aminotransferase (ALT) level ≤ 2.5 x IULN, and alkaline phosphatase ≤ 2.5 x IULN.
c. Adequate renal function defined as creatinine ≤ 1.5 x IULN OR calculated creatinine clearance ≥ 50 mL/min for subjects with creatinine levels > 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 ≤ 1.5 x IULN (unless the subject is receiving anticoagulant therapy); and activated partial thromboplastin time (aPTT) ≤ 1.5 x IULN (unless the subject is receiving anticoagulant therapy)
7. Other than the cancer for which the subject is enrolled, 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, or has undergone potentially curative therapy with no evidence of that disease recurrence for 5 years since initiation of that therapy.
8. In Phase 2, subjects must provide a sufficient and adequate formalin-fixed paraffin embedded (FFPE) tumor tissue sample preferably from the most recent biopsy of a tumor lesion, collected either at the time of or after the diagnosis of advanced or metastatic disease has been made AND from a site not previously irradiated. If no tumor tissue is
available, a fresh biopsy will be required. (See Section 6.4.2.1 for details.)
Note: Tissue from needle or excisional biopsy or from resection is required.
9. Female subjects must have a negative serum pregnancy test at screening (within 72 hours before first dose of study drug) if of childbearing potential or be of non-child bearing potential. Non-childbearing potential is defined as (by other than medical reasons):
a. ≥ 45 years of age and has not menstruated for greater than 1 year,
b. Amenorrheic for < 2 years without a hysterectomy and oophorectomy and a folliclestimulating hormone (FSH) value in the postmenopausal range upon pretrial (screening) evaluation,
c. Whose status is post hysterectomy, oophorectomy or tubal ligation. |
|
| E.4 | Principal exclusion criteria |
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 before the first dose of treatment.
2. Has an inadequate washout period prior to first dose of study drug defined as:
a. Received systemic cytotoxic chemotherapy or biological therapy within 3 weeks before first dose,
b. Received radiation therapy within 3 weeks before first dose, or
c. Had major surgery within 4 weeks before first dose.
3. Has received prior therapy with:
a. 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
b. For Phase 2: > 1 systemic treatment regimen for the advanced (recurrent, unresectable, or metastatic) cervical cancer for which the subject is considered for the study
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 NCI CTCAE Grade > 1 severity.
Note: Sensory neuropathy or alopecia of 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 fully human monoclonal antibodies (National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 [NCI CTCAE] Grade ≥ 3), any history of anaphylaxis, or uncontrolled asthma.
7. Is receiving systemic corticosteroid ≤ 7 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. Examples of permitted therapy are daily prednisone at doses of 5 to 7.5 mg or equivalent hydrocortisone dose, and steroid therapy administered by topical, intraocular, intranasal, and/or inhalation routes.
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 evidence of stable supra-tentorial lesions at screening (based on 2 sets of brain images, performed ≥ 4 weeks apart, and obtained after the brain metastases treatment). In addition, any neurologic symptoms that developed either as a result of the brain metastases or their treatment must have resolved or be minimal and be expected as sequelae from treated lesions. For individuals who received steroids as part of brain metastases treatment, steroids must be discontinued ≥ 7 days prior to first dose of study drug.
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 before enrollment, unstable angina, congestive heart failure (New York Heart Association class ≥ 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.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1
- Occurrence of DLTs in subjects in dose escalation during the first 21 days of treatment
- Frequency, severity, and duration of treatmentemergent adverse events (TEAEs) and laboratory abnormalities using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03.
Phase 2
- Confirmed ORR per RECIST 1.1, as determined by an IERC, in the analysis population |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| As per protocol section 6 |
|
| E.5.2 | Secondary end point(s) |
Phase 1
- PK profile.
- Receptor occupancy on circulating T cells measured 4 hours after the 1st dose and immediately prior to the 2nd dose
- Receptor occupancy saturation levels correlated with AGEN2034 PK exposure metrics
- Antidrug antibody (ADA) concentrations and correlation with AGEN2034 PK exposure metrics
Phase 2
- Frequency, severity, and duration of TEAEs and laboratory abnormalities, using NCI CTCAE v4.03.
- PK profile
- ADA concentrations and correlation with AGEN2034 PK exposure metrics
- Confirmed ORR per RECIST 1.1, as determined by an investigator
- DOR 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 after last tumor assessment). Subjects without an event at analysis cutoff date will be censored on date of last tumor assessment.
- DCR, defined as proportion of subjects with complete response (CR), partial response (PR), or stable disease (SD) for at least 12 weeks
- Duration of SD, measured from the start of treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started, including baseline measurements.
- Time to response, defined as the time from the first dose date to first observation of confirmed response.
- PFS time, defined as time from first treatment administration to first observation of documented disease progression (or death within 12 weeks after 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.
- Median OS and OS rate
- OS time, defined as time from start of 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 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| As per protocol section 6 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Tolerability, Biological and Clinical Activity of AGEN2034 |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 24 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Belgium |
| Brazil |
| Estonia |
| France |
| Lithuania |
| Poland |
| Spain |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| If the trial is not terminated prematurely, the end of the trial is defined as 1 year after the last subject has received the last dose of AGEN2034 |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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