| 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 |
• To assess the safety and tolerability of AGEN2034 and to determine the maximum tolerated dose (MTD) of AGEN2034 in subjects with metastatic or locally advanced solid tumors (Phase 1 safety cohort).
• To assess the best overall response (BOR) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) in subjects with recurrent, unresectable, or metastatic cervical cancer that has progressed after a platinum doublet administered for treatment of advanced disease (Phase 2 efficacy expansion cohort). |
|
| E.2.2 | Secondary objectives of the trial |
• To characterize the pharmacokinetic (PK) profile of AGEN2034 and to correlate exposure with target occupancy.
• To evaluate the immunogenicity of AGEN2034 and to correlate it to exposure and biological activity.
• To assess the duration of response and progression-free survival (PFS) per RECIST 1.1.
• To assess overall survival (OS) rate within a 1-year time frame.
• To evaluate the association between BOR and tumor expression of programmed cell death protein 1 ligand 1 (PD-L1). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion Criteria: Dose Escalation (Safety Cohort)
1. Signed written informed consent.
2. Age ≥ 18 years.
3. Histologically or cytologically proven metastatic or locally advanced solid tumors for which no standard therapy exists or standard therapy has failed. Availability of tumor archival material or fresh biopsies is optional for subjects in dose escalation.
4. ECOG performance status of 0 to 1 at trial entry and estimated life expectancy of ≥ 3 months.
5. Evidence of objective disease. A measurable lesion is not necessary.
6. Adequate hematological function, defined as white blood cell (WBC) count ≥3 × 10e9/L; absolute neutrophil count (ANC) ≥ 1.5 × 10e9/L; lymphocyte count ≥ 0.5 × 10e9/L; platelet count ≥100 × 10e9/L; and hemoglobin ≥ 9 g/dL (may have been transfused).
7. Adequate hepatic function, defined as total bilirubin ≤ 1.5 × upper limit of normal (ULN); AST≤ 2.5 × ULN; and ALT ≤2.5 × ULN. For subjects with documented metastatic disease to the liver, AST and ALT: ≤5 × ULN.
8. Adequate renal function, defined as estimated creatinine clearance >50 mL/min according to Cockcroft-Gault formula or measured 24-hour creatinine clearance (or local institutional standard method).
9. Effective contraception for both male and female subjects if risk of conception exists (Section 0).
Inclusion Criteria: Expansion (Efficacy Cohort)
1. Signed written informed consent.
2. Age ≥18 years.
3. Subjects must have recurrent, unresectable, or metastatic cervical cancer, and have relapsed after a platinum-containing doublet administered for treatment of advanced (recurrent, unresectable, or metastatic) disease.
Subjects must have persistent, recurrent, or metastatic squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix, with documented disease progression (disease not amendable to curative therapy).
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.
Subjects must have had one prior systemic chemotherapeutic regimen for management of persistent, recurrent, or metastatic carcinoma of the cervix (e.g., paclitaxel/cisplatin, paclitaxel/cisplatin/ bevacizumab). Chemotherapy administered concurrently with primary radiation (e.g., weekly cisplatin) is not counted as a systemic chemotherapy regimen. 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).
Note: Subjects who have received >1 prior regimen are not eligible.
4. ECOG performance status of 0 to 1 at trial entry and an estimated life expectancy of ≥3 months.
5. Availability of a formalin-fixed paraffin-embedded block containing tumor tissue or 7 unstained tumor slides suitable for PD-L1 expression assessment.
6. Availability of tissue for HPV testing (paraffin block or one 7-μm section on a slide).
7. Disease must be measurable, with ≥1 unidimensional measurable lesion per RECIST 1.1.
8. Adequate hematological function, defined as WBC ≥3 × 10e9/L; ANC ≥1.5 × 10e9/L; lymphocyte count ≥0.5 × 10e9/L; platelet count ≥100 × 10e9/L; and hemoglobin ≥9 g/dL (may have been transfused).
9. Adequate hepatic function, defined as total bilirubin ≤1.5 × ULN; AST ≤2.5 × ULN; and ALT ≤2.5 × ULN.
10. Adequate renal function, defined as estimated creatinine clearance >30 mL/min according to Cockcroft-Gault formula or measured 24-hour creatinine clearance (or local institutional standard method).
11. Effective contraception for both male and female subjects if risk of conception exists.
|
|
| E.4 | Principal exclusion criteria |
Exclusion Criteria (Dose Escalation and Expansion Cohorts)
1. Concurrent treatment with a non-permitted drug (Section 6.5.2).
2. 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. For subjects with metastatic melanoma, prior treatment with CTLA-4–blocking antibody is permissible.
3. Concurrent anticancer treatment (e.g., cytoreductive therapy, radiotherapy except for palliative bone-directed radiotherapy, immune therapy, or cytokine therapy except for erythropoietin) within 28 days before start of trial treatment; major surgery within 28 days before start of trial treatment (excluding prior diagnostic biopsy); use of hormonal agents within 7 days before start of trial treatment, except for subjects with castration-resistant prostate cancer, who may remain on treatment with luteinizing hormone–releasing hormone agonists or antagonists; or use of any investigational drug within 28 days before start of trial treatment.
Note: Small molecule or antibody targeted therapy is permissible <14 days from start of trial treatment.
4. Subjects receiving immunosuppressive agents (such as steroids) for any reason should be tapered off these drugs 14 days before initiation of study treatment. Steroids with no or minimal systemic effect (topical, inhalation) are allowed.
Note: Subjects receiving bisphosphonate or denosumab are eligible provided that treatment was initiated ≥14 days before first dose of AGEN2034.
Note: Use of inhaled or topical corticosteroid use is permitted.
Note: Steroid pre-medication for radiographic imaging for dye allergies is permitted.
5. Previous malignant disease (other than target malignancy to be investigated in this trial) within last 5 years, with the exception of basal or squamous cell carcinoma of the skin.
6. Rapidly progressive disease.
7. Active or history of central nervous system metastases.
8. Receipt of any organ transplantation, including allogeneic stem-cell transplantation.
9. Significant acute or chronic infections, including:
• Known history of testing positive for HIV or known acquired immunodeficiency syndrome (AIDS).
• Positive test for HBV surface antigen and/or confirmatory HCV RNA (if anti-HCV antibody tested positive).
10. Active or history of any autoimmune disease (subjects with diabetes type 1, vitiligo, psoriasis, hypo-, or hyperthyroid disease not requiring immunosuppressive treatment are eligible) or immunodeficiencies.
11. Known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE grade ≥3), any history of anaphylaxis, or uncontrolled asthma (i.e., ≥3 features of partly controlled asthma).
12. Persisting toxicity related to prior therapy of grade >1 severity per NCI-CTCAE. Sensory neuropathy of grade ≤2 is acceptable.
13. Pregnancy or breast-feeding.
14. Known alcohol or drug abuse.
15. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (<6 months before enrollment), myocardial infarction (<6 months before enrollment), unstable angina, congestive heart failure (New York Heart Association class ≥II), or serious uncontrolled cardiac arrhythmia requiring medication.
16. All other significant diseases (e.g., inflammatory bowel disease) that, in the opinion of the investigator, might impair the subject’s tolerance of trial treatment.
17. Any psychiatric condition that would prohibit understanding or rendering of informed consent.
18. Legal incapacity or limited legal capacity.
19. Vaccination within 4 weeks of first dose of AGEN2034 and while on study except for administration of inactivated vaccines (e.g., inactivated influenza vaccines).
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Occurrence of dose-limiting toxicity (DLTs) during first 3 weeks of treatment in the dose escalation part of the trial.
2. Confirmed BOR per RECIST 1.1, as adjudicated by IERC, for subjects enrolled in the second-line cervical cancer expansion cohort only. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Best response obtained among all tumor assessment visits after start of trial treatment until documented disease progression |
|
| E.5.2 | Secondary end point(s) |
1. PK profile.
2. PFS time, defined as time from first IMP administration to first observation of documented disease progression (or death within 12 weeks of last tumor assessment), per RECIST 1.1 and investigator assessment. Subjects without an event at analysis cutoff date will be censored on date of last tumor assessment.
3. BOR per RECIST 1.1 and investigator assessment, and immune-related BOR per immune-related response criteria and investigator assessment.
4. Duration of response per RECIST 1.1 and investigator assessment, 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.
5. 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.
6. For efficacy expansion cohort: Unconfirmed response at week 13 per RECIST 1.1 based on investigator assessment.
7. For efficacy expansion cohort: Duration of response per RECIST 1.1, as adjudicated by IERC.
8. For efficacy expansion cohort: PFS time per RECIST 1.1, as adjudicated by IERC. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Cycle 1 (Day 1,2, 8); Cycle 2 (Day 1, 2, 8) , Cycle 3 Day1,8, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1, Cycle 7 Day 1, Cycle 8 Day 1, End of treatment Visit, Final safety visit
2. Time from first IMP administration to first observation of documented disease progression
3. Best response obtained among all tumor assessment visits after start of trial treatment until documented disease progression
4. Time from first observation of response to first observation of documented disease progression
5. Time from first administration of trial treatment to death
6. Week 13
7. Week 13
8. Time from first IMP administration to first observation of documented disease progression |
|
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 |
|
| 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 | 7 |
| E.8.9.1 | In the Member State concerned days | 17 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 22 |
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