E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced/metastatic malignancies, and preferred indications: head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), esophageal cancer, gastric cancer, melanoma, renal cell cancer, pancreatic cancer, cervical cancer, and triple negative breast cancer (BC) |
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E.1.1.1 | Medical condition in easily understood language |
selected advanced malignancies |
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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 | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10015362 |
E.1.2 | Term | Esophageal cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10063916 |
E.1.2 | Term | Metastatic gastric cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 | 10008229 |
E.1.2 | Term | Cervical cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10075566 |
E.1.2 | Term | Triple negative breast cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 | 10077738 |
E.1.2 | Term | Hepatocellular carcinoma metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10033609 |
E.1.2 | Term | Pancreatic carcinoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10038389 |
E.1.2 | Term | Renal cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10025650 |
E.1.2 | Term | Malignant melanoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10017758 |
E.1.2 | Term | Gastric cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10060121 |
E.1.2 | Term | Squamous cell carcinoma of head and neck |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029515 |
E.1.2 | Term | Non-small cell lung cancer recurrent |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 | 10007416 |
E.1.2 | Term | Carcinoma liver |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 characterize the safety and tolerability of KY1044 as single agent and in combination with atezolizumab and to identify recommended doses for future studies.
Phase 2: To estimate the anti-tumor efficacy of KY1044 as single agent and in combination with atezolizumab. |
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E.2.2 | Secondary objectives of the trial |
- To evaluate the preliminary anti-tumor activity of KY1044 as single agent and in combination with atezolizumab (Phase 1 only) - To characterize the safety and tolerability of KY1044 as single agent and in combination with atezolizumab (Phase 2 only) - To characterize the PK profile of KY1044 as single agent and in combination with atezolizumab - To assess emergence of anti-KY1044 and anti-atezolizumab antibodies following one or more i.v. infusions of KY1044 single agent and/or in combination with atezolizumab - To assess changes in biomarkers - To describe the survival rate at 12 and 24 months of patients treated with KY1044 as single agent and in combination with atezolizumab for each disease group |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients eligible for inclusion in this study must meet all of the following criteria: 1. Written informed consent must be obtained prior to any procedures 2. Age ≥18 years (≥20 years in Taiwan) 3. Histologically documented advanced/metastatic malignancies 4. Phase 1 and Phase 2 patients with advanced/metastatic malignancies who have measurable disease (non-measurable disease is allowed only in Phase 1) as determined by RECIST 1.1 (refer to Appendix 2) will be eligible if, according to the NCCN guidelines, there are no available therapies known to confer a clinical benefit for their disease, or they have exhausted all such available options. Additionally, the following specific tumor indications will be enrolled: a. Phase 1 (including enrichment part): Patients with advanced/metastatic malignancies, and preferred indications as identified in Section 3.1 (NSCLC, HNSCC, HCC, melanoma, cervical, gastric/esophageal, gastric, renal, pancreatic, and triple negative BC) b. Phase 2 KY1044 single agent: Patients with advanced/metastatic malignancies in indications in which signs of anti tumor activity (CR, PR or durable SD with tumor shrinkage that does not qualify for PR) were seen during the dose escalation of KY1044 as single agent. c. Phase 2 KY1044 in combination with atezolizumab: Patients with advanced/metastatic malignancies in the below selected indications, and/or indications which have shown promising activity in Phase 1: • NSCLC (anti PD (L)1 therapy naïve and pre treated) • Gastric/Esophageal (anti PD (L)1 therapy naïve and pre treated) • HNSCC (anti PD (L)1 therapy naïve and pre treated) • Esophageal (anti PD (L)1 therapy naïve and pre treated) • Cervical (anti PD (L)1 therapy naïve and pre treated) Indications, in which signs of anti tumor activity has been observed in Phase 1 with KY1044 in combination with atezolizumab 5. Prior therapy with anti-PD-(L)1 inhibitors is allowed provided any toxicity attributed to prior anti-PD-(L)1-directed therapy did not lead to discontinuation of therapy 6. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 7. Life expectancy longer than 12 weeks 8. Must have a site of disease amenable to biopsy, and be a candidate for tumor biopsy according to the treating institution’s guidelines. Patient must be willing to undergo a new tumor biopsy at screening, and during therapy on the study 9. Females of child bearing potential must be using two highly effective contraceptive measures for the duration of study participation and for at least 5 months after discontinuing study treatment, or longer if the half-life of KY1044 is observed to exceed that of atezolizumab (see Section 5.8). Females must not be breast feeding and must have a negative pregnancy test prior to start of dosing or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening: - Post-menopausal defined as aged ≥50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments - Women less than 50 years old would be considered postmenopausal if they have been amenorrhoeic for at least 12 months following the cessation of exogenous hormonal treatments, and have serum follicle-stimulating hormone and luteinizing hormone levels in the postmenopausal range for the institution - Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation 10. For the duration of study participation and for at least 5 months after discontinuing study treatment, or longer if the half-life of KY1044 is observed to exceed that of atezolizumab sexually active males must use barrier contraception (i.e., condoms). |
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E.4 | Principal exclusion criteria |
Patients eligible for this study must not meet any of the following criteria: 1. Presence of symptomatic CNS metastases, or CNS metastases that require local CNS-directed therapy, or increasing doses of corticosteroids within the prior 2 weeks of first dose of study treatment. Patients with treated brain metastasis unless neurologically stable (for 4 weeks post-treatment and prior to study enrolment) and off of steroids for at least 2 weeks before the first dose of study treatment 2. History of severe hypersensitivity reactions to other mAbs and/or their excipients 3. Known presence of neutralizing anti-atezolizumab antibodies (for patients previously treated with atezolizumab) 4. Having out of range laboratory values (creatinine, bilirubin, ALT, AST, Absolute neutrophil count , Platelet count, Hemoglobin) 5. Impaired cardiac function or clinically significant cardiac disease, including any of the following: - Clinically significant and/or uncontrolled heart disease such as congestive heart failure requiring treatment, uncontrolled hypertension or clinically significant arrhythmia - QTcF >470 msec on screening ECG or congenital long QT syndrome - Acute myocardial infarction or unstable angina pectoris <3 months prior to first dose of study treatment 6. Known human immunodeficiency virus (HIV), active hepatitis B virus (HBV) or active hepatitis C virus (HCV) infection. Patients with any severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection. 7. Malignant disease, other than that being treated in this study. 8. Any medical condition that would, in the Investigator’s judgment, prevent the patient’s participation in the clinical study due to safety concerns, compliance with clinical study procedures or interpretation of study results 9. Active autoimmune disease or a documented history of autoimmune disease 10. Patients previously exposed to anti-PD-(L)1 treatment who are not adequately treated for skin rash or had no replacement therapy for endocrinopathies should be excluded 11. Patients with a history of drug-induced pneumonitis or current pneumonitis 12. Systemic steroid therapy or any immunosuppressive therapy. Topical, inhaled, nasal, and ophthalmic steroids are not prohibited 13. Herbal preparations/medications (including, but not limited to: St. John’s Wort, kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone, yohimbe, saw palmetto, and ginseng) are prohibited from the time that patients enter the screening period (at least 7 days prior to first dose of study treatment) until the last dose of study treatment (3 weeks for St John’s Wort) 14. Warfarin and other types of long acting anticoagulants (such as phenprocumon and or anti Xa inhibitors with a half life of >12 hours) is prohibited within 4 weeks of the first dose of study treatment and patients requiring anticoagulant treatment should switch to low molecular weight heparin or anti Xa inhibitors with a half life of ≤12 hours. 15. Use of life attenuated vaccines against infectious diseases within 4 weeks of the first dose of study treatment 16. Systemic anti-cancer therapy within 2 weeks of the first dose of study treatment. For cytotoxic agents that have major delayed toxicity, 4 weeks is indicated as washout period 17. Major surgery within 2 weeks of the first dose of study treatment 18. Anti-CTLA4, anti-PD-(L)1 treatment within 4 weeks of the first dose of study treatment 19. Pre-treatment with anti-CTLA4 antibodies in combination with any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathway 20. Participation in an interventional, investigational study within 4 weeks of the first dose of study treatment 21. Presence of CTCAE v5 ≥Grade 2 toxicity (except alopecia, peripheral neuropathy and ototoxicity, which are excluded if CTCAE v5 ≥Grade 3) due to prior cancer therapy 22. Use of hematopoietic colony-stimulating growth factors ≤2 weeks prior to start of study treatment. An erythroid stimulating agent is allowed if it was initiated at least 2 weeks prior to the first dose of study treatment and the patient is on a stable dose 23. Radiotherapy within 2 weeks of the first dose of study treatment, except for palliative radiotherapy to a limited field, such as for the treatment of bone pain or a focally painful tumor mass. To allow evaluation for response to treatment, patients enrolled in the Phase 2 part must have remaining measurable disease that has not been irradiated. 24. Pregnant or lactating women. In rare cases of an endocrine-secreting tumor, hCG levels may be above normal limits, but without existing pregnancy. In these cases, there should be a repeat serum beta-hCG test (with a non-rising result) and a vaginal/pelvic ultrasound to rule out pregnancy. Upon confirmation of results and discussion with the Medical Monitor, these patients may enter the study. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Phase 1 - Safety: Incidence and severity of AEs and SAEs, including changes in laboratory parameters, vital signs and electrocardiograms (ECGs) - Tolerability: Dose interruptions, reductions and dose intensity - The incidence of DLTs with KY1044 as single agent during the first 21 days of treatment - The incidence of DLTs with KY1044 in combination with atezolizumab during the first 21 days of treatment
Phase 2 - ORR per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase 1 Safety evaluation and assessment of AEs throughout the study
Phase 2 Tumor Imaging RECIST 1.1: at screening, every 8 weeks (±7 days) after the start of treatment for the first 16 weeks, after that every 12 weeks (±7 days) till the end of 24 months of treatment or until objective disease progression |
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E.5.2 | Secondary end point(s) |
Efficacy measures: - Best Overall Response (BOR), PFS and Duration of Response (DOR) per RECIST 1.1; - ORR and PFS per immune-related (i)RECIST (Phase 1 and Phase 2) - ORR per RECIST 1.1 (Phase 1 only) - Survival rate at 12 and 24 months Safety: - Safety: Incidence and severity of AEs and SAEs, including changes in laboratory parameters, vital signs and ECGs (Phase 2) 2. Tolerability: Dose interruptions, reductions and dose intensity (Phase 2) PK measures; KY1044 PK measures (e.g., Cmax, half-life); Serum concentration vs. time profiles Anti-drug antibodies; Presence and/or concentration of anti-KY1044 and anti-atezolizumab antibodies Biomarkers |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy measures: - Tumor Imaging RECIST 1.1: at screening, every 8 weeks after the start of treatment for the first 16 weeks, after that every 12 weeks till the end of 24 months of treatment or until objective disease progression Safety: - Safety evaluation and assessment of AEs throughout the study - Tolerability assessed throughout the study PK measures; PK samples will be taken pre- and post-dose during all cycles and unscheduled at any time, when clinically indicated Anti-drug antibodies; ADA samples are collected at every cycle at pre-dose on Day 1 and unscheduled at any time, when clinically indicated Biomarkers |
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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 | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
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 | 2 |
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 | 16 |
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 |
Italy |
Taiwan |
United Kingdom |
United States |
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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
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The completion of the study is defined as the last visit for the last patient on treatment (for patients, who stopped treatment earlier follow-up will be ended at this point). |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 1 |
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 | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |