Anal Cancer, Biliary Tract Cancer, Bladder Cancer, Cervical Cancer, Gastric Cancer, Head and Neck Squamous Cell Carcinoma, Hepatocellular Carcinoma, Melanoma, Merkel Cell Carcinoma, Mesothelioma, Microsatellite Instability High, Non Small Cell Lung Cancer, Ovarian Cancer, Renal Cell Carcinoma, Skin Squamous Cell Carcinoma, Small-cell Lung Cancer, Thymic Cancer, Thyroid Cancer, Triple Negative Breast Cancer
Conditions
Keywords
Thyroid Cancer, Renal Cell Carcinoma, Non Small Cell Lung Cancer, Small-cell Lung Cancer, Bladder Cancer, Melanoma, Merkel Cell Carcinoma, Skin Squamous Cell Carcinoma, Microsatellite Instability High, Triple Negative Breast Cancer, Mesothelioma, Thymic Cancer, Cervical Cancer, Biliary Tract Cancer, Hepatocellular Carcinoma, Ovarian Cancer, Gastric Cancer, Head and Neck Squamous Cell Carcinoma, Anal Cancer
Brief summary
A multicenter open-label phase 1/1b study to evaluate the safety and preliminary efficacy of nanrilkefusp alfa as monotherapy and in combination with pembrolizumab in patients with selected advanced/metastatic solid tumors
Detailed description
This study will assess the safety and tolerability of nanrilkefusp alfa administered as monotherapy and in combination with an anti-PD-1 antibody (pembrolizumab) in patients with selected relapsed/refractory advanced/metastatic solid tumors (renal cell carcinoma, non-small cell lung cancer, small-cell lung cancer, bladder cancer, melanoma, Merkel-cell carcinoma, skin squamous-cell carcinoma, microsatellite instability high solid tumors, triple-negative breast cancer, mesothelioma, thyroid cancer, thymic cancer, cervical cancer, biliary tract cancer, hepatocellular carcinoma, ovarian cancer, gastric cancer, head and neck squamous-cell carcinoma, and anal cancer).
Interventions
A fusion protein which consists of the N-terminal sushi domain of human IL-15 receptor α covalently coupled via a linker of 20 amino acids to human IL-15
DRUGPembrolizumab
A humanized IgG4 monoclonal antibody with high specificity of binding to the PD-1 receptor
Sponsors
SOTIO Biotech AG
SOTIO Biotech a.s.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with selected histologically or cytologically confirmed advanced and/or metastatic solid tumors who are refractory to or intolerant of existing therapies known to provide clinical benefit for their condition. * ECOG performance score 0-1. Patients with ECOG performance score 2 to be discussed with the sponsor's medical monitor to be agreed for inclusion. * Estimated life expectancy of ≥3 months * Washout periods: 4 weeks for chemotherapy, 4 weeks or 5 half-lives (whichever shorter) for biologic agents including immuno-oncology therapy and 4 weeks from major surgeries, definitive radiotherapy and 2 weeks after palliative radiotherapy * At least one measurable lesion per iRECIST in a non-irradiated port. If in a previously irradiated port, must have demonstrated progression since best response to radiation therapy. * Have fully recovered from previous treatment to grade ≤1 toxicity (excluding alopecia) or have stable grade 2 neuropathy * Adequate organ system function * Negative serum pregnancy test, if woman of child-bearing potential (non-childbearing is defined as greater than one year postmenopausal or surgically sterilized). * Accessible tumor tissue available for fresh biopsy
Exclusion criteria
* Untreated central nervous system metastases and/or leptomeningeal carcinomatosis * Known additional malignancy that is progressing and/or requires active treatment * Prior exposure to drugs that are agonists of IL-2- or IL-15-like but not limited to rhIL-15 (NCI), ALT-803 (ALTOR), NKTR-214 (Nektar) * History of and current interstitial lung disease or fibrosis and pneumonitis; patients with clinically significant or oxygen requiring chronic obstructive pulmonary disease or any chronic inflammatory disease (sarcoidosis etc.) * Has received a live vaccine within 30 days of planned start of study therapy * Absolute white blood cell count ≤2.0 ×10e9/L * Absolute neutrophil count ≤1.0 ×10e9/L * Platelet count ≤100×10e9/L * Pregnant or breastfeeding women * Any active autoimmune disease or a documented history of autoimmune disease, poorly controlled asthma, or history of syndrome that required systemic steroids (except the allowed doses) or immunosuppressive medications, except for patients with vitiligo or resolved childhood asthma/atopy * Specific co-morbidities * Parts B and B1: * Is hypersensitive to any of the ingredients of pembrolizumab drug product (KEYTRUDA®) * History of solid organ transplantation or hematopoietic stem cell transplantation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose-limiting Toxicities (DLTs) | Through Cycle 1 (21 days) | * Grade (gr) 5 not related to disease progression or other causes * Gr ≥3 non-hematologic toxicity; exceptions: gr 3 nausea, vomiting or diarrhea controlled in 72 hours; gr 3 fatigue \<5 days; gr ≥3 correctable electrolyte abnormalities \<72 hours and no clinical complications; gr ≥3 amylase or lipase without clinical pancreatitis * Hy's law cases * Gr 3 AST or ALT or gr 3 bilirubinemia \>5 days * Hematologic DLTs: gr 4 neutropenia or thrombocytopenia \>7 days, febrile neutropenia, gr ≥3 thrombocytopenia with bleeding * Gr 4 immune-related AEs * Gr 3 or 4 non-infectious pneumonitis * Gr 3 immune-related AEs, excluding colitis, hepatitis, and pneumonitis, not downgrading to gr ≤2 in 3 days despite maximal supportive care including systemic corticosteroids or to gr 1 or baseline in 14 days * Gr 2 pneumonitis not downgrading to gr 1 in 3 days * Gr 3 colitis * Part B and Part B1: Recurrent grade 2 pneumonitis |
| Number of Participants With Adverse Events (AEs) | Day 1 up to approximately 2 years and 2.5 months | Nanrilkefusp alfa related only |
| Number of Participants With Serious AEs (SAEs) | Day 1 up to approximately 2 years and 2.5 months | Nanrilkefusp alfa related only |
| Number of Participants With AEs Leading to Premature Discontinuation of Nanrilkefusp Alfa | Day 1 up to approximately 2 years and 2.5 months | Nanrilkefusp alfa related only |
| Number of Participants Who Died | Day 1 up to approximately 2 years and 2.5 months | Nanrilkefusp alfa-related deaths only |
| Number of Participants With Nanrilkefusp Alfa-related Clinical Laboratory Test Abnormalities (Coagulation; Hematology; Clinical Chemistry; Urinalysis; Thyroid and Cardiac Function) | Day 1 up to approximately 2 years and 2.5 months | The following laboratory parameters were assessed: * Coagulation: Prothrombin time, activated partial thromboplastin time, international normalized ratio, D-dimer, fibrinogen * Hematology: Hemoglobin, hematocrit, red blood cell count, reticulocytes, white blood cell count (with full differentiation), absolute lymphocyte count, platelet count * Clinical chemistry: Na, K, Cl, phosphate, Mg, Ca, albumin, total protein, ALT, AST, bilirubin (direct, total), alkaline phosphatase, lactate dehydrogenase, creatinine clearance, creatinine, glucose (preferably fasting), urea or blood urea nitrogen, cholesterol, triglyceride, CRP, uric acid, amylase, lipase * Urinalysis: pH, glucose, protein, bilirubin, urobilinogen. Microscopic examination: red blood cell count, white blood cell count, epithelial cells, bacteria * Thyroid function: TSH, free triiodothyronine (T3), free thyroxine (T4) * Cardiac function: Cardiac troponin T |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Nanrilkefusp Alfa Concentration Profile, Cycle 1 Day 1 | Cycle 1 Day 1 | This outcome measure presents the overall nanrilkefusp apfa Cmax profile over Cycle 1 Day 1. |
| Overall Activation Levels of Ki-67+ CD8+ T Cells on Day 6 of Cycle 1 | Cycle 1 Day 6 | The eCRF Hematology data (specifically white blood cell count (WBC)) for each timepoint will be used to derive the Cell counts in 10\^9/L. Once merged with the pharmacodynamic data by subject and timepoint, the following will be used as derivation: • Ki-67+ Cells of CD8+ Cells (10\^9/L) = Ki-67+ Cells of CD8+ Cells (%CD45+) x 0.01 x WBC" Absolute count of Ki-67+ Cells was calculated as percentage of those cells out of CD45+ multiplied by WBC and 0.01. |
| Overall Activation Levels of Ki-67+ CD8+ CD45RO+ CD45RA- T Cells on Day 6 of Cycle 1 | Cycle 1 Day 6 | The eCRF Hematology data (specifically white blood cell count (WBC)) for each timepoint will be used to derive the Cell counts in 10\^9/L. Once merged with the pharmacodynamic data by subject and timepoint, the following will be used as derivation: * Ki-67+ Cells of CD8+ Cells (10\^9/L) = Ki-67+ Cells of CD8+ Cells (%CD45+) x 0.01 x WBC * CD45RO+ CD45RA- (Memory) Cells of CD8+ Cells (10\^9/L) = CD45RO+ CD45RA- (Memory) Cells of CD8+ Cells (%CD45+) x 0.01 x WBC Absolute count of Ki-67+ Cells was calculated as percentage of those cells out of CD45+ multiplied by WBC and 0.01. Absolute count of CD45RO+ CD45RA- (Memory) Cells was calculated as percentage of those cells out of CD45+ multiplied by WBC and 0.01. |
| Overall Activation Levels of Ki-67+ CD4+ T Cells on Day 6 of Cycle 1 | Cycle 1 Day 6 | The eCRF Hematology data (specifically white blood cell count (WBC)) for each timepoint will be used to derive the Cell counts in 10\^9/L. Once merged with the pharmacodynamic data by subject and timepoint, the following will be used as derivation: • Ki-67+ Cells of CD4+ Cells (10\^9/L) = Ki-67+ Cells of CD4+ Cells (%CD45+) x 0.01 x WBC Absolute count of Ki-67+ Cells was calculated as percentage of those cells out of CD45+ multiplied by WBC and 0.01. |
| Overall Activation Levels of Ki-67+ NK Cells on Day 6 of Cycle 1 | Cycle 1 Day 6 | The eCRF Hematology data (specifically white blood cell count (WBC)) for each timepoint will be used to derive the Cell counts in 10\^9/L. Once merged with the pharmacodynamic data by subject and timepoint, the following will be used as derivation: • Ki-67+ Cells of CD3-CD56+ (NK) Cells (10\^9/L) = Ki-67+ Cells of CD3-CD56+ (NK) Cells (%CD45+) x 0.01 x WBC Absolute count of Ki-67+ Cells was calculated as percentage of those cells out of CD45+ multiplied by WBC and 0.01. |
| Overall Activation Levels of Ki-67+ NKT Cells on Day 6 of Cycle 1 | Cycle 1 Day 6 | The eCRF Hematology data (specifically white blood cell count (WBC)) for each timepoint will be used to derive the Cell counts in 10\^9/L. Once merged with the pharmacodynamic data by subject and timepoint, the following will be used as derivation: • CD3+CD56+ (NKT) Cells of CD45+ Live Cells (10\^9/L) = CD3+CD56+ (NKT) Cells of CD45+ Live Cells (%) x 0.01 x WBC Absolute count of Ki-67+ Cells was calculated as percentage of those cells out of Live Cells multiplied by WBC and 0.01. |
| Overall Activation Levels of Ki-67+ Treg Cells on Day 6 of Cycle 1 | Cycle 1 Day 6 | The eCRF Hematology data (specifically white blood cell count (WBC)) for each timepoint will be used to derive the Cell counts in 10\^9/L. Once merged with the pharmacodynamic data by subject and timepoint, the following will be used as derivation: • Ki-67+ Cells of Treg Cells (10\^9/L) = Ki-67+ Treg Cells (%CD45+) x 0.01 x WBC" Absolute count of Ki-67+ Cells was calculated as percentage of those cells out of CD45+ multiplied by WBC and 0.01. |
| Objective Response Rate | Day 1 up to approximately 5 years 5 months | Based on investigator review of radiographic images according to Response Evaluation Criteria In Solid Tumors for immune-based therapeutics (iRECIST). Objective response rate according to iRECIST was defined as the percentage of participants with complete response according to iRECIST or partial response according to iRECIST for target lesions and assessed by CT/MRI. |
| Duration of Response | Day 1 up to approximately 5 years 5 months | Duration of response according to iRECIST was defined as time to disease progression for participants with partial response or complete response according to iRECIST for target lesions and assessed by CT/MRI. |
| Clinical Benefit Rate | Day 1 up to approximately 5 years 5 months | Based on investigator review of radiographic images according to iRECIST. Clinical benefit rate according to iRECIST was defined as the percentage of patients with partial responses, complete responses, and stable disease according to iRECIST for target lesions and assessed by CT/MRI. |
| Progression-free Survival | Day 1 up to approximately 5 years 5 months | Progression-free survival according to iRECIST was defined as the time from the first day of study treatment to the first date of radiological disease progression according to iRECIST or death. |
| Number of Participants With Anti-drug Antibodies at the End of Treatment | Day 1 until 30 (±2) days after the last dose of nanrilkefusp alfa, up to approximately 5 years 5 months | — |
Countries
Czechia, France, Spain, United States
Contacts
PRINCIPAL_INVESTIGATORStephane Champiat, Dr.
Institute Gustave Roussy, Villejuif, France
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 70 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 3 Participants |
| Region of Enrollment Czechia | 8 participants |
| Region of Enrollment France | 3 participants |
| Region of Enrollment Spain | 2 participants |
| Region of Enrollment United States | 0 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk | EG015 affected / at risk | EG016 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 3 | 2 / 3 | 2 / 3 | 2 / 4 | 2 / 3 | 2 / 4 | 2 / 6 | 3 / 4 | 2 / 5 | 1 / 3 | 0 / 3 | 0 / 3 | 4 / 7 | 0 / 3 | 1 / 5 | 0 / 4 | 19 / 52 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 4 / 4 | 3 / 3 | 4 / 4 | 6 / 6 | 4 / 4 | 5 / 5 | 3 / 3 | 3 / 3 | 3 / 3 | 7 / 7 | 3 / 3 | 5 / 5 | 4 / 4 | 52 / 52 |
| serious Total, serious adverse events | 2 / 3 | 2 / 3 | 1 / 3 | 3 / 4 | 0 / 3 | 2 / 4 | 1 / 6 | 2 / 4 | 3 / 5 | 1 / 3 | 1 / 3 | 2 / 3 | 6 / 7 | 2 / 3 | 2 / 5 | 2 / 4 | 26 / 52 |
Outcome results
None listed