E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Locally Advanced or Metastatic Solid Tumor Malignancies |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10065143 |
E.1.2 | Term | Malignant solid tumour |
E.1.2 | System Organ Class | 100000004864 |
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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 |
- To evaluate the safety and tolerability, and define the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of NKTR-214 in combination with nivolumab or in combination with nivolumab and other anti-cancer therapies - To evaluate the efficacy of NKTR-214 in combination with nivolumab or in combination with nivolumab and other anti-cancer therapies by assessing the objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) at the RP2D |
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E.2.2 | Secondary objectives of the trial |
- To evaluate the efficacy of NKTR-214 in combination with nivolumab or in combination with nivolumab and other anti-cancer therapies by assessing overall survival (OS), progression-free survival (PFS), clinical benefit rate (CBR), and duration of response (DOR) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Under Amendment 7, the study is closed to patient screening and enrollment. For Dose Escalation and Dose Expansion (Parts 1 + 2) 1. Provide written, informed consent to participate in the study and follow study procedures 2. Male/female patients, age 18 years or older at the time of signing ICF 3. Life expectancy >12 weeks 4. Patients must not have received prior IL 2 therapy 5. ECOG performance status 0 or 1 6. Measurable disease per RECIST 1.1 7. Demonstrated adequate organ function, as defined below, within 14 days of treatment initiation a. WBC count ≥2000/μL (after at least 7d without growth factor support) b. ANC ≥1500/μL (after at least 7d without growth factor support) c. Platelet count ≥100 × 103/μL (no transfusions allowed within 7d of C1D1 to meet entry criteria) d. Hemoglobin ≥ 9.0 g/dL (no transfusions allowed within 7d of C1D1 to meet entry criteria) e. Serum creatinine ≤ 2 mg/dL (or glomerular filtration rate ≥ 40 mL/min); patients with urothelial carcinoma who are cisplatin ineligible (creatinine clearance < 60 mL/min) may be enrolled if the glomerular filtration rate is ≥ 30 mL/min. f. AST and ALT ≤ 3× upper limit of normal (ULN) g. Total bilirubin within normal limits (total bilirubin ≤ 2× ULN if associated with hepatobiliary metastases or Gilbert’s syndrome) h. Lipase and amylase ≤ 1.5× ULN. Patients with pancreatic metastases and lipase and/or amylase < 3× ULN may enroll. Patients may not enroll if there are clinical or radiographic signs of pancreatitis. 8. A documented LVEF > 45% using standard echocardiogram or MUGA scan test within 60 days prior to Cycle 1 Day 1. 9. Oxygen saturation ≥ 92% on room air 10. Clinically significant toxic effect(s) of the most recent prior anti-cancer therapy must be Grade 1 or resolved (except alopecia and sensory neuropathy); patients with Grade 2 adrenal insufficiency related to prior anti-cancer therapy (defined as requiring medical intervention, such as concomitant steroids) or Grade 2 hypothyroidism (defined as requiring hormone replacement therapy) may be enrolled provided that clinical symptoms are adequately controlled and the daily dose is 10 mg or less of prednisone or equivalent. If the patient received major surgery or radiation therapy of > 30 Gy, they must have recovered from the toxicity and/or complications from the intervention. 11. Women of childbearing potential (WCBP) must agree and commit to the use of to use highly effective methods of birth control throughout the duration of the study until 6 months following the last dose of study drug. Acceptable methods are defined as those that result, alone or in combination, in a low failure rate (i.e., less than 1% per year) when used consistently and correctly, such as surgical sterilization, an intrauterine device, or hormonal contraception in combination with a barrier method. It is currently unknown whether NKTR-214 may reduce the effectiveness of systemically acting hormonal contraceptives, and therefore women using systemically acting hormonal contraceptives should add a barrier method. In certain countries (if permitted by law), WCBP may agree to abide by heterosexual sexual abstinence during the time of participation in this study. 12. Male patients and their female partners of childbearing potential must agree and commit to use a double-barrier contraception (e.g., condom with spermicidal foam/gel/film/cream/suppository) throughout the duration of the study until 6 months following the last dose of study drug; in addition to their female partner using either an intrauterine device or hormonal contraception and continuing until 6 months following the last dose of study drug. This criterion is not applicable for male patients who have had a vasectomy > 6 months before signing ICF. 13. Patients must not have active brain metastases: a. Participants with brain metastases are eligible if these have been treated and there is no MRI evidence of progression for at least 8 weeks after treatment is complete and within 28d prior to first dose of study treatment administration. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study treatment administration. Stable dose of anticonvulsants is allowed. Treatment for CNS metastases may include stereotactic radiosurgery (e.g. GammaKnife, CyberKnife, or equivalent) or neurosurgical resection. Patient who received whole brain radiation therapy are not eligible. b. No new or progressing brain metastasis of any size d. No stereotactic radiation or craniotomy within 4 weeks of Cycle 1 Day 1 e. No new central nervous system lesions on repeat radiographic imaging 4 weeks or more from last treatment f. No clinically significant symptoms secondary to brain metastases g. Head imaging must occur on study in accordance with Section 5.7.
Please refer to the protocol for a detailed list of the inclusion criteria |
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E.4 | Principal exclusion criteria |
Under Amendment 7, the study is closed to patient screening and enrollment. 1. Use of an investigational agent or an investigational device within 28 days before administration of first dose of study drug 2. Females who are pregnant or breastfeeding 3. Patients who have an active, known or suspected autoimmune disease. Patients requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease that requires systemic steroids or immunosuppressive agents. (Exceptions include any patient on 10 mg or less of prednisone or equivalent, patients with vitiligo, hypothyroidism stable on hormone replacement, Type I diabetes, Graves’ disease, Hashimoto's disease, alopecia areata, eczema, or with Medical Monitor approval) 4. History of allergy or hypersensitivity to study drug components 5. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in situ cervical cancer. An incidental finding of prostate cancer (identified upon resection of the prostate) is acceptable, provided that the following criteria are met: Stage T2N0M0 or lower; Gleason score ≤ 6, and prostate-specific antigen (PSA) below lower limit of normal by local laboratory. 6. History of organ or tissue transplant that requires systemic use of immune suppressive agents 7. Evidence of clinically significant interstitial lung disease or active, noninfectious pneumonitis 8. Prior surgery or radiotherapy within 14 days of therapy. Patients must have recovered from all radiation-related toxicities and not require corticosteroids. 9. Patients who have had < 28 days since the last chemotherapy, biological therapy, or < 14 days from approved tyrosine kinase inhibitor (TKI) therapy (sunitinib, sorafenib, vemurafenib, dabrafenib, cobimetinib, erlotinib, gefitinib, afatinib, osimertinib), < 14 days from last dose of hormonal therapy (for patients with breast cancer), or systemic or inhaled steroid therapy at doses greater than 10 mg of prednisone or equivalent before administration of the first dose of study drug. 10. Parts 1 and 2 Patients in whom prior anti PD-1 / anti-PD-L1 therapy was intolerable and required discontinuation of treatment 11. NSCLC patients who require supplemental oxygen 12. Uveal melanoma is excluded 13. Active infection requiring systemic therapy 14. Has known hepatitis B virus (HBV) infection (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C virus (HCV) infection (e.g., HCV ribonucleic acid [RNA] qualitative is detected) 15. Has known immunodeficiency or active human immunodeficiency virus (HIV 1/2 antibodies) 16. Prolonged Fridericia's corrected QT interval (QTcF) > 450 ms for men and > 470 ms for women at Screening 17. History of unstable or deteriorating cardiac disease or cerebrovascular disease within the previous 2 years prior to screening including but not limited to the following: a. Unstable angina or myocardial infarction b. Congestive heart failure (New York Heart Association [NYHA] Class III or IV) c. Uncontrolled clinically significant arrhythmias d. Prior cerebrovascular accident or transient ischemic attack. 18. Need for > 2 antihypertensive medications for management of hypertension (including diuretics) 19. Known current drug or alcohol abuse 20. Any condition including medical, emotional, psychiatric, or logistical that, in the opinion of the Investigator, would preclude the patient from adhering to the protocol or would increase the risk associated with study participation or study drug administration or interfere with the interpretation of safety results (e.g., a condition associated with diarrhea or acute diverticulitis).
For sites located in the United Kingdom only Patients cannot enroll in the five cohorts with the combination of NKTR-214 + nivolumab + other anti-cancer therapies. (Cohorts 3d.1, 3d.2, 3e, 5b, 5c). |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoints of the study are to determine the MTD of NKTR-214 in combination with nivolumab or in combination with nivolumab and ipilimumab
The primary efficacy measurement is the ORR per RECIST 1.1 based on data provided by the Investigator’s assessment using the response evaluable population. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety assessments will be monitored throughout the study
Efficacy assessments - tumour assessents: screening, every 8 weeks ± 7 days from cycle 2 onwards |
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E.5.2 | Secondary end point(s) |
ORR using RECIST 1.1 BOR using RECIST 1.1 TTR using RECIST 1.1 DOR using RECIST 1.1 CBR using RECIST 1.1 Overall Survival (OS) PFS using RECIST 1.1 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Tumour assessents: screening, every 8 weeks ± 7 days from cycle 2 onwards, end of treatment, at follow up
Immunogenicity: screening, Day 1 of every cycle, end of treatment, at follow up |
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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 | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
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 | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Safety, tolerability, efficacy |
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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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 32 |
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 |
Belgium |
Canada |
France |
Hong Kong |
Italy |
Poland |
Spain |
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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End of study is defined as no more than 3 years after the last patient received their first dose of NKTR-214 or Sponsor decision to terminate the study, whichever comes first. |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 0 |