| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Phase 1 – Part A dose escalation in patients with locally advanced, recurrent and/or metastatic solid tumor for which no standard therapy exists or standard therapy has failed.
Phase 2 - Part B advanced cervical cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
Phase 1 – Part A advanced solid tumor (cancer)
Phase 2 - Part B cervical cancer |
|
| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10008236 |
| E.1.2 | Term | Cervical cancer stage IV |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065147 |
| E.1.2 | Term | Malignant solid tumor |
| 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:
• assess safety and tolerability of AGEN1884 in combination with AGEN2034 in subjects with locally advanced, recurrent and/or metastatic solid tumors.
Phase 2:
• Phase 2: To assess ORR (objective Response rate) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as determined by the IERC. |
|
| E.2.2 | Secondary objectives of the trial |
Phase 1:
• characterize pharmacokinetic (PK) profiles of AGEN1884 and AGEN2034
• correlate AGEN1884 and AGEN2034 exposure with target occupancy
• evaluate immunogenicity of AGEN1884 in combination with AGEN2034 and assess potential impact on PK exposure and biological activity
Phase 2:
• assess the safety and tolerability of AGEN1884 in combination with AGEN2034 in subjects with locally advanced, recurrent, and/or metastatic solid Tumors
• characterize PK profile of AGEN1884 and AGEN2034
• evaluate immunogenicity of AGEN1884 in combination with AGEN2034 and assess potential impact on PK exposure and biological activity
• assess ORR according to RECIST 1.1 as determined by investigator
• assess DOR, disease control rate (DCR), duration of SD, time to response, and PFS time per RECIST 1.1
• assess OS |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Optional pharmacogenomics research. |
|
| E.3 | Principal inclusion criteria |
1. Voluntarily agree to participate by giving written informed consent.
Participation in pharmacogenomics testing is optional.
2. ≥18 years of age.
3. Diagnosis:
a. Phase 1 – Male or female having histologically or cytologically confirmed diagnosis of a locally advanced, recurrent, and/or metastatic solid tumor for which no standard therapy is available or standard therapy has failed.
b. Phase 2 -
I. Female having (1) a histologically or cytologically confirmed diagnosis of squamous-cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of
the cervix, and (2) locally advanced, recurrent, and/or metastatic 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 locally advanced, recurrent, and/or metastatic disease;
Note: Subjects who only received platinum-based chemotherapy concurrently
with primary radiation (e.g., weekly cisplatin) or 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 first line.
4. Measurable Disease
a. Phase 1: objective evidence of disease; presence of measurable disease is not required.
b. Phase 2: measurable disease on imaging based on RECIST version 1.1.
5. life expectancy of at least 3 months and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6. adequate organ function as indicated by laboratory values.
7. Other than the cancer for which the subject is enrolled, no history of prior malignancy, with exception of basal cell carcinoma of skin, superficial bladder cancer, squamous-cell carcinoma of skin, or undergone potentially curative therapy with no evidence of that disease recurrence for 5 years since initiation of that therapy.
8. In Phase 2, sufficient and adequate formalin fixed tumor tissue sample. |
|
| E.4 | Principal exclusion criteria |
1. 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 first dose of treatment.
2. received 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 locally advanced,
recurrent, and/or metastatic cervical cancer for which the subject is considered for the study. Subjects who received a systemic regimen immediately after
progressing within 6 months of completing chemotherapy concurrent with primary radiation or adjuvant chemotherapy after radiation will only be considered as having 1 prior systemic regimen for the purpose of this criterion.
4. persisting toxicity related to prior therapy of National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 (NCICTCAE)
Grade >1 severity.
5. Is expected to require any other form of systemic or localized antineoplastic therapy while on trial (including maintenance therapy with another agent, adiation therapy, and/or surgical resection).
6. Has known severe hypersensitivity reactions to fully human monoclonal antibodies (NCI-CTCAE Version 4.03 Grade ≥3), any history of anaphylaxis, or uncontrolled asthma
7. Is receiving systemic corticosteroid therapy ≤ 7 days prior to the first dose of study treatment or receiving any other form of systemic immunosuppressive
medication (corticosteroid use on study for management of immune-related AEs, 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 study 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 immunosuppressive systemic treatment.
10. allogeneic tissue/solid organ transplant.
11. interstitial lung disease (ILD) OR has had a history of pneumonitis that has required oral or IV corticosteroids.
12. active infection requiring intravenous systemic therapy.
13. known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
14. 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. clinically significant (i.e., active) cardiovascular disease |
|
| 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 treatment-emergent AEs (TEAEs) and laboratory abnormalities using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.03.Occurrence of DLTs in subjects in dose escalation during the first 21 days of treatment.
Phase 2:
•Confirmed ORR per RECIST 1.1, as determined by the IERC, in the analysis population. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
• Phase 1: during the first 21 days of treatment.
• Phase 2: throughout the study. |
|
| E.5.2 | Secondary end point(s) |
Phase 1:
• AGEN1884 and AGEN2034 PK parameters which may include (but are not limited to) maximum observed concentration at steady-state (Cmax-ss), minimum observed concentration at steady-state (Cmin-ss), area under the drug concentration-time curve within time span t1 to t2 at steady-state (AUC(t1-t2)-ss), area under the drug concentration-time curve from time zero to time t (AUC(0-t)), area under the drug concentration-time curve from time zero to infinity (AUC(0-∞)), time to maximum observed concentration (tmax), terminal
disposition rate constant (λz), terminal elimination half-life (t1/2), systemic clearance (CL), and volume of distribution (Vd)
• Receptor occupancy on circulating T cells measured 4 hours after the first dose and immediately prior to the second dose
• Receptor occupancy saturation levels correlated with AGEN1884 and GEN2034 PK exposure metrics
• ADA concentrations and potential impact on AGEN1884 and AGEN2034 PK exposure metrics
Phase 2:
• Frequency, severity, and duration of TEAEs and laboratory abnormalities, using NCI-CTCAE v4.03.
• AGEN1884 and AGEN2034 PK parameters which may include (but are not limited to) Cmax-ss, Cmin-ss, AUC(t1-t2)-ss, AUC(0-t), AUC(0-∞), tmax, λz, t1/2, L, and Vd.
• ADA concentrations and potential impact on AGEN1884 and 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 be censored on date of last tumor assessment.
• DCR, defined as proportion of subjects with CR, PR, or 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 |
|
| 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 | Yes |
| 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 | Yes |
| 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 |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| The trial is a phase Ib/II study. Phase I is phase Ib, Phase 2 is phase II |
|
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| part Phase I is a dose-escalation and Phase II is the expansion cohort. |
|
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 21 |
| 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 |
| Brazil |
| Hungary |
| Poland |
| Spain |
| Ukraine |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| 24 months after the last subject has received the last planned treatment dose. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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