| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally Advanced or Metastatic Solid Tumor Malignancies |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 20.1 |
| 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 |
|
| 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.
- To evaluate the efficacy of NKTR 214 in combination with nivolumab by assessing the objective response rate (ORR) by RECIST 1.1 at the RP2D.
|
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the efficacy of NKTR 214 in combination with nivolumab by assessing overall survival (OS) and progression-free survival (PFS).
- To evaluate the efficacy of NKTR 214 in combination with nivolumab by assessing immune-related RECIST (irRECIST) at the RP2D.
- To assess the immunological effects and to accommodate disease-specific pharmacodynamics markers such as lactate dehydrogenase (LDH) (e.g., in melanoma), of NKTR 214 when administered in combination with nivolumab.
- To characterize the pharmacokinetics (PK) of nivolumab and NKTR 214 and metabolites.
- To assess the development of anti-drug antibodies against NKTR-214 and nivolumab when administered in combination.
- To assess the association between efficacy measures and PD-L1 expression in tumors. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
For Dose Escalation (Part 1) and Dose Expansion (Part 2):
1. Willing and able to provide written informed consent
2. Histologically confirmed diagnosis of a locally advanced (not amenable to curative therapy such as surgical resection) or metastatic melanoma, RCC, NSCLC, urothelial carcinoma, or TNBC
3. Male or female patients, age 18 years or older at the time of signing the informed consent form (ICF)
4. Life expectancy >12 weeks
5. Patients must not have received prior interleukin 2 (IL 2) therapy
6. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
7. Measurable disease per RECIST 1.1
8. Demonstrated adequate organ function, as defined below, within 14 days of treatment initiation
a. White blood cell (WBC) count ≥ 2000/μL (after at least 7 days without growth factor support or transfusion)
b. Absolute neutrophil count (ANC) ≥ 1500/μL (after at least 7 days without growth factor support or transfusion)
c. Platelet count ≥ 100 × 103/μL (transfusions allowed)
d. Hemoglobin ≥ 9.0 g/dL (transfusions allowed)
e. Serum creatinine ≤ 2 mg/dL (or glomerular filtration rate ≥ 40 mL/min)
f. Aspartate aminotransferase (AST) and alanine transaminase (ALT) ≤ 3× upper limit of normal (ULN)
g. Total bilirubin within normal limits unless associated with hepatobiliary metastases or Gilbert’s syndrome, in that case total bilirubin ≤ 2× ULN
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.
9. On stress echocardiogram, documented left ventricular ejection fraction > 45% on cardiac stress test within 60 days prior to Cycle 1 Day 1. At the discretion of the Investigator, patients who are unable to perform a stress echocardiogram may instead have a multigated acquisition (MUGA) scan or transthoracic echocardiogram (TTE).
10. Oxygen saturation ≥ 92% on room air
11. Clinically significant toxic effect(s) of the most recent prior chemotherapy must be resolved to Grade 1 or less (except alopecia and sensory neuropathy). 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.
12. Women of childbearing potential (WCBP) must agree 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.
13. Males with female partners of child-bearing potential must agree to use a 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 may be waived for male subjects who have had a vasectomy > 6 months before signing the informed consent form (ICF).
14. Patients with stable brain metastases may be enrolled, provided:
a. No prior brain metastasis lesion greater than 2 cm
b. No new or progressing brain metastasis of any size
c. No stereotactic radiation or craniotomy within 4 weeks of Cycle 1 Day 1
d. No new central nervous system lesions on repeat radiographic imaging 4 weeks or more from last treatment
e. No treatment with systemic steroids (> 10 mg of prednisone daily or equivalent) within 2 weeks of Cycle 1 Day 1
f. No clinically significant symptoms secondary to brain metastases
15. Sample of fresh baseline tumor biopsies (fresh baseline biopsy is defined as a biopsy specimen taken during screening) is required, except if inaccessible and with Medical Monitor approval. Patients must also consent to allow acquisition of existing formalin-fixed paraffin-embedded (FFPE) material (archival tumor tissue), either a block or unstained slides for performance of correlative studies.
Please refer to the protocol for a detailed list of the inclusion criteria |
|
| E.4 | Principal exclusion criteria |
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. Active malignancy not related to the current diagnosed malignancy
6. History of organ transplant that requires use of immune suppressive agents
7. Use of warfarin within 14 days of initiating study drug (Note: Low molecular weight heparin is allowed on the study)
8. Evidence of clinically significant interstitial lung disease or active, noninfectious pneumonitis
9. Prior surgery or radiotherapy within 14 days of therapy. Patients must have recovered from all radiation-related toxicities, not required corticosteroids and have not had radiation pneumonitis.
10. 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), 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.
11. Patients in whom prior checkpoint inhibitor therapy was intolerable and required discontinuation of treatment
12. NSCLC patients who require supplemental oxygen
13. Active infection requiring systemic therapy
14. Has known hepatitis B virus (HBV) infection (e.g., HBsAg reactive) or hepatitis C virus (HCV) infection (e.g., HCV RNA qualitative is detected)
15. Has known immunodeficiency or active human immunodeficiency virus (HIV 1/2 antibodies)
16. Prolonged QTcF > 450 ms for men and > 470 ms for women at Screening
17. History of unstable or deteriorating cardiac disease within the previous 6 months 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
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 |
|
| 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.
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. |
|
| 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 |
|
| 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 |
|
| 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 |
|
| 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 |
|
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| 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 |
| Denmark |
| France |
| Italy |
| Poland |
| Spain |
| Sweden |
| Ukraine |
| United Kingdom |
| 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
|
| 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. |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| 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 |
Print
