| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed or refractory (R/R) head and neck squamous cell carcinoma (HNSCC) or colorectal carcinoma (CRC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Head and neck squamous cell cancer or colorectal cancer which has spread to other part of body |
|
| 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 | 10009963 |
| E.1.2 | Term | Colon carcinoma recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10007336 |
| E.1.2 | Term | Carcinoma colon recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 22.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10082179 |
| E.1.2 | Term | Squamous cell carcinoma of head and neck metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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) |
|
| 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 1b (Dose Escalation):
• To evaluate the safety, tolerability, and define the maximum tolerated dose (MTD), and/or RP2D of NKTR-255 in combination with cetuximab in R/R metastaticHNSCC or CRC.
Phase 2 (Dose Expansion):
• To evaluate the safety and tolerability of NKTR-255 in patients with R/R metastatic HNSCC or CRC.
• To evaluate the efficacy of NKTR-255 in combination with cetuximab in R/R metastatic HNSCC or CRC by assessing the objective response rate (ORR) by RECIST 1.1. |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the anti-tumor activity of the combination of NKTR-255 and cetuximab by assessing progression-free survival(PFS) and overall survival (OS).
• To characterize the pharmacodynamic (PD) effects and change from baseline in immune cell populations (natural killer [NK], CD8+ cells, and other immune populations), tumor cells, cytokine levels, and changes in gene expression after administration of NKTR-255 in combination with cetuximab.
• To characterize the pharmacokinetics (PK) of NKTR-255 and cetuximab.
• To assess development of anti-drug antibodies against NKTR-255. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion Criteria for All Patients
1. Patients must be at least 18 years of age at study entry
2. Patients must be capable of understanding and providing a written informed consent.
3. Women of childbearing potential (WCBP) must have a negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) at Screening and a negative serum or urine pregnancy test within 24 hours prior to dosing. Women of childbearing potential and men who are sexually active with women of childbearing potential must commit to use contraception.
4. Histologically confirmed diagnosis of a locally advanced (not amenable to curative therapy such as surgical resection) or metastatic cancer of the following histologies: HNSCC or CRC
5. Patients who have previously received cetuximab or other EGFR-directed therapies are excluded from Phase 2 of the trial, unless cetuximab was given as part of a primary treatment approach, with no progressive disease for at least 4 months following the end of prior cetuximab treatment.
6. Life expectancy > 12 weeks as determined by the Investigator
7. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
8. Measurable disease per RECIST 1.1
9. Patients must have demonstrated adequate organ function during Screening:
a. Estimated glomerular filtration rate ≥ 40 mL/min/1.73m2 calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Creatinine Equation
Inclusion Criteria for Specific Tumor Types
• Head and Neck Cancer
1. Patients must have histologically or cytologically confirmed advanced, recurrent, or metastatic HNSCC that could not be treated with curative intent. “Advanced” is defined as either locally advanced HNSCC not amenable to curative surgery or radiotherapy or with distant metastases.
2. Progression (or toxicity precluding additional treatment) on any first or second line platinum-based chemotherapy and/or anti-PD-1 or programmed death-ligand 1 (anti-PD-L1) (together termed "anti-PD-(L)1") antibody
3. Patients who have undergone treatment with anti-PD-(L)1 antibody must have had the last dose of antibody at least 4 weeks prior and evidence of tumor progression before they can be enrolled into this study.
4. Ineligible for platinum-based (either cisplatin or carboplatin) chemotherapy or chemoradiation due to decline in renal function and/or patient's intolerance
5. Must have known status by pathology for human papillomavirus (HPV) and Epstein-Barr virus (EBV) in HNSCC, either metastatic or recurrent disease.
• Colorectal Cancer
1. Patients must have a histologically or cytologically confirmed diagnosis of advanced CRC; patients in Phase 2 must have confirmed KRAS wild type EGFR-expressing advanced CRC. “Advanced” is defined as either locally advanced unresectable cancer or metastatic disease.
2. Patients must have received or were intolerant to at least 2 prior cancer therapy regimens administered for metastatic disease.
3. Patients with high microsatellite instability (MSI-H) or mismatched repair disease (dMMR) tumors must have been exposed to checkpoint inhibitors such as anti-PD-(L)1 or anticytotoxic T-lymphocyte-associated protein (CTLA)-4 antibody. |
|
| E.4 | Principal exclusion criteria |
1.Use of an IMP or an investigational device within 28 days before administration of first dose of study drug(s)
2.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 corticosteroids or immunosuppressive.
3.History of allergy or known hypersensitivity to murine protein or study drug components
4.History of organ transplant that requires ongoing use of immunosuppressive agents
5.Patients who have been previously treated with IL-2 or IL-15
6.Patients with HNSCC who require treatment with anticoagulation therapy are not eligible.
7.Contraindication to or unable to receive cetuximab
8.Patient has had prior Grade 4 IRR to cetuximab
9.Unresolved toxicity from previous anti-cancer therapy, unless resolved to Grade ≤ 1; or resolved to Grade 2; or resulting from incomplete recovery from surgery
10.Prior surgery or radiotherapy within 14 days of initiating study drug(s). Patients must have recovered from all radiation-related toxicities.
11.Patients participating in observational studies should be discussed with the Medical Monitor to confirm eligibility.
12.Patients who have had < 28 days since the last anti-cancer treatment, chemotherapy or biological therapy, or < 14 days from approved tyrosine kinase inhibitor therapy, 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(s).
13.Patients who have received systemic interferon alpha within the previous 6 months prior to enrollment in the study are not eligible.
14.Active infection requiring systemic therapy within 7 days prior to dosing
15.Evidence of clinically significant interstitial lung disease or active, noninfectious pneumonitis
16.Known immunodeficiency or active human immunodeficiency virus (HIV)
17.Known to be seropositive or active for hepatitis B or hepatitis C
18.QTcF> 450 ms for men and > 470 ms for women at Screening
19. History of unstable or deteriorating cardiac disease within the previous 6 months prior to Screening
20.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.
21.Patient has any of the following laboratory test results during Screening:
a.AST and ALT level ≥ 2.5 times ULN;
b.Alkaline phosphatase level ≥ 2.5 × ULN;
c.Total bilirubin level ≥ 2 × ULN;
d.Potassium level < 3.0 mEq/L; or
e.Corrected serum calcium > 14.0 mg/dL (3.5 mmol/L)
22.Patient is a woman who is pregnant or breastfeeding or planning to become pregnant while enrolled in this study or within 4 weeks after the last dose of NKTR-255 or within 2 months after the last dose of cetuximab.
23.Active brain metastases or leptomeningeal metastases patients with brain metastases are eligible if these have been treated and there is no radiographic evidence of progression for at least 4 weeks after treatment is complete. There must also be no requirement for immunosuppressive doses of systemic corticosteroids for at least 4 weeks prior to study treatment. Stable dose of anticonvulsants is required within 14 days prior to study treatment. Treatment for central nervous system metastases may include stereotactic radiosurgery or neurosurgical resection. Patients who received whole brain radiation therapy are not eligible.
24.Patients with hypertension must be on a stable anti-hypertensive regimen for the 14 days prior to study treatment; Screening blood pressure must be < 150 mmHg for systolic blood pressure and < 90 mmHg for diastolic blood.
25.Known current drug or alcohol abuse
26.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) |
1. Incidence of Treatment-Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) of NKTR-255 with Cetuximab:
Safety and tolerability of NKTR-255 in combination with cetuximab as evaluated by dose limiting toxicities, incidence of drug-related Adverse Events (AEs), SAEs, and AEs leading to discontinuation, deaths, and clinical laboratory abnormalities per CTCAE 5.0
2.Efficacy of NRTR-255 with Cetuximab:
Efficacy of NKTR-255 in combination with cetuximab in R/R metastatic HNSCC or CRC by assessing the objective response rate (ORR) by RECIST 1.1
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Safety and tolerability: throughout the trial till 60 days after the last dose of study treatment
2. Efficacy: Through study completion, an expected average of 1 year |
|
| E.5.2 | Secondary end point(s) |
Efficacy of NKTR-255 with Cetuximab:
Evaluate the anti-tumor activity of the combination of NKTR-255 and cetuximab by assessing progression-free survival (PFS) and overall survival (OS). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Through study completion, an expected average of 1 year |
|
| 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 | Yes |
| 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 |
|
| 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 |
| DOSE ESCALATION AND DOSE EXPANSION |
|
| 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.8.3 |
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 | 8 |
| 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 |
| United States |
| France |
| Italy |
| Spain |
|
| 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
|
| End of study is defined as no more than 2 years after the last patient received his or her last dose of NKTR-255 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 | 6 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 6 |
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