| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Relapsed/refractory patients with advanced solid tumors : metastatic colorectal cancer (CRC) or metastatic ovarian cancer or metastatic castration-resistant prostate cancer (mCRPC) or metastatic pancreatic ductal adenocarcinoma (PDAC).
Metastatic or unresectable refractory melanoma
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| E.1.1.1 | Medical condition in easily understood language |
Relapsed/refractory patients with metastatic cancer : colorectal or ovarian or prostate or pancreatic ductal adenocarcinoma
Metastatic or unresectable refractory melanoma |
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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 | 10052362 |
| E.1.2 | Term | Metastatic colorectal 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 | 10057529 |
| E.1.2 | Term | Ovarian cancer 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10076506 |
| E.1.2 | Term | Castration-resistant prostate 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 | LLT |
| E.1.2 | Classification code | 10033599 |
| E.1.2 | Term | Pancreatic adenocarcinoma 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027481 |
| E.1.2 | Term | Metastatic melanoma |
| 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 |
Part I
Characterize the overall safety and tolerability profile of a range of intravenous (IV) doses of ICT01 in combination with low-dose subcutaneous (LDSC) IL-2 in patients with advanced solid tumors tumors and in combination with LDSC-IL-2 and pembrolizumab in patients with advanced melanoma or pancreatic ductal adenocarcinoma (PDAC).
Part II
Characterize the preliminary antitumor activity according to RECIST of IV ICT01 in combination with LDSC IL-2 in patients with a specific solid tumor indication with or without pembrolizumab (up to 2 indications for Part 2 will be determined after Part 1). |
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| E.2.2 | Secondary objectives of the trial |
Part I
1. Characterize the pharmacodynamic activity of ICT01 in combination with LDSC IL-2 to increase the number and activation status of γ9δ2-T cells in the blood and tumors of patients with advanced solid tumors and in combination with pembrolizumab in patients with advanced melanoma or PDAC.
2. Characterize the preliminary anti-tumor activity according to Response Evaluation Criteria In Solid Tumors (RECIST)of a range of IV doses of ICT01 in combination with LDSC IL-2 in patients with advanced solid tumors and in combination with pembrolizumab in patients with advanced melanoma or PDAC.
Part II
1. Characterize the overall safety and tolerability of IV ICT01 in combination with LDSC IL-2 with or without pembrolizumab.
2. Characterize the PD activity of ICT01 in combination with LDSC IL-2 with or without pembrolizumab to increase the number and activation status of γ9δ2-T cells in the blood and tumors of patients with a specific solid tumor indication. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion Criteria for Part 1
The following criteria must be checked during the screening period and at baseline. ALL inclusion criteria must be met to include the subject in the study:
1) Male or female aged ≥18 years
2) Voluntarily signed written informed consent before performance of any study-related screening procedures
3) Relapsed/refractory patients who have failed at least 2 lines of systemic therapy or who failed first line therapy and are intolerant of or have a contraindication to the standard second line of therapy with histologically or cytologically confirmed diagnosis of:
a. metastatic colorectal cancer (CRC)
i. patients must have progressed after receiv-ing fluoropyrimidine, oxaliplatin, and iri-notecan and an antiangiogenic agent.
ii. patients with tumors known to be MSI-H, prior therapy with a checkpoint inhibitor is required if they were clinically able to re-ceive it.
iii. patients with epidermal growth factor re-ceptor (EGFR)-expressing, RAS wild-type should have received anti EGFR therapy.
b. metastatic ovarian cancer
i. patients must be platinum resistant and must have had at least one treatment line after being resistant to platinum chemo-therapy
c. metastatic castration-resistant prostate cancer (mCRPC)
d. metastatic pancreatic ductal adenocarcinoma (PDAC)
e. metastatic or unresectable refractory melanoma with primary resistance following at least 6 weeks of prior CPI treatment, defined as best response of progressive disease or SD of short duration (lasting less than 6 months), as per Society for Immunotherapy of Cancer [SITC] Immunotherapy Resistance Taskforce
4) Availability of baseline tumor biopsy and willingness to undergo on-study tumor biopsies
5) Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
6) Life expectancy > 3 months as assessed by the Investigator
7) Clinical labs:
a. Hematology:
- Hemoglobin ≥8.5 g/dL (equal to 5.28 mmol/L; transfusion dependent or independent);
- platelet count ≥100 × 109/L;
- lymphocyte count ≥0.5 × 109/L;
- absolute neutrophil count ≥1.0 × 109/L;
- White Blood Count (WBC) ≥ 4 × 109/L
b. Liver enzymes:
- aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5 × upper limit of normal (ULN) (<5 × ULN in the case of liver metastases);
- bilirubin ≤1.5 × ULN (<2 × ULN in case of liver metastases);
c. Renal function: serum creatinine <1.5 × ULN or creatinine clearance ≥ 50 mL/min (Cockcroft and Gault) for serum creatinine ≥1.5x ULN.
8) Pulse oximetry of 95% or higher at rest, unless patient has chronic lung disease where 90% or higher at rest is acceptable
9) Contraceptives measures
a. Women of childbearing potential must:
i. have a negative pregnancy test within 1 week before first dose of study drug
ii. use highly effective method(s) of birth control consistently and correctly during the study and for at least 4 months after the last dose of study drug
iii. agree to not donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for at least 4 months after the last dose of study
iv. agree to no plan to breastfeed and no plan to become pregnant during the study and for at least 4 months after the last dose of study drug.
b. Males must:
i. agree to use a condom with spermicidal foam/gel/film/cream/suppository when sexually active during the study and for at least 4 months after the last dose of study drug
ii. agree to not donate sperm during the study and for at least 4 months after the last dose of study drug
iii. no plan to father a child during the study or within 4 months after the last dose of study drug.
10) Women must not be breastfeeding
11) At least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST)
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| E.4 | Principal exclusion criteria |
The following criteria must be checked during the screening period and at baseline. If ANY exclusion criterion applies, the subject must not be included in the study:
1) Any malignancy of γ9δ2 T cell origin
2) Any systemic anti-tumor-directed drug therapy within 28 days or 5 times the elimination half-life (whichever is shorter) before study treatment
3) Treatment with investigational drugs within 28 days before study treatment , or 5 half-lives
4) Systemic steroids at a daily dose of > 10 mg of prednisone, > 2 mg of dexamethasone or equivalent, for the last 28 days and ongoing
5) Patients with rapidly progressing disease defined as advanced/metastatic, symptomatic, visceral spread, with a risk of life-threatening complications in the short term (e.g., during Screening Period/ treatment washout) that includes patients with massive uncontrolled effusions pleural, pericardial, peritoneal, pulmonary lymphangitis, and over 50% liver involvement
6) Ongoing immune-related adverse events (irAEs) ≥grade 2 not resolved from previous therapies except vitiligo, stable neuropathy up to grade 2, hair loss, and stable endocrinopathies with substitutive hormone therapy.
7) Ongoing systemic autoimmune disease requiring systemic immunosuppressive therapy
8) Primary or secondary immune deficiency
9) Active and uncontrolled infections requiring intravenous antibiotic or antiviral treatment
10) Known/suspected hypersensitivity against ICT01, human or humanized IgGs, IL-2 (Proleukin®), pembrolizumab or their excipients
11) Seropositive (except after vaccination or confirmed cure for hepatitis) for human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV)
12) Clinically significant cardiac disease including heart failure (New York Heart Association, Class III or IV), pre-existing arrhythmia, uncontrolled angina pectoris, or myocardial infarction within 1 year before study entry
13) Dementia or altered mental status that would prohibit informed consent
14) Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study assessed by the Investigator
15) Active drug or alcohol abuse as assessed by the Investigator
16) Patients with uncontrolled and symptomatic brain metastases or seizure disorders. Patient with asymptomatic brain metastases are allowed provided they are stable and off therapeutic steroids for at least 4 weeks
17) Patients who have received vaccination with a live-attenuated vaccine within 30 days prior to study treatment initiation
18) Patients with contraindications to IL-2 according to the SmPC, including organ allografts and pre-existing severe major organ dysfunction.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Part I
The primary objective of safety and tolerability will be evaluated in this study by the incidence, severity, and relationship of the following endpoints during the study: DLTs, TEAEs, fatal TEAEs, TESAEs, TEAEs leading to discontinuation of study treatment or treatment modifications; and incidence and severity of clinically significant findings on clinical laboratory tests, vital signs, ECGs, and physical examinations.
Part II
Primary endpoint: Disease control rate (DCR) comprising patients with stable disease, partial response or complete response per RECIST1.1. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Ongoing throughout the duration of the study |
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| E.5.2 | Secondary end point(s) |
Part I
• PD endpoint will be the change from baseline in counts and activation status of γ9δ2 T cells in PBMCs and tumor biopsies, with a significant expansion of circulating γ9δ2 T cells, and an increase in γ9δ2 T cells in the tumor biopsies at Day 28, considered key PD endpoints.
• The preliminary antitumor activity endpoint will be DCR as per RECIST. If appropriate, Objective response rate (ORR), time to progression (TTP), progression-free survival (PFS) and overall survival (OS) will also be analyzed as endpoints. iRECIST will be considered exploratory and used for treatment decisions.
Part II
● The secondary endpoints relating to the primary objective are ORR, TTP, PFS and OS according to RECIST.
● The key secondary safety endpoints will be evaluated by incidence, severity, and relationship of DLTs, TEAEs, fatal TEAEs, TESAEs, TEAEs leading to discontinuation of study treatment, and TEAEs leading to discontinuation of study; and clinically significant findings on clinical laboratory tests, vital signs, ECGs, and physical examinations.
● PD: Change from baseline in counts and activation status of γ9δ2 T cells in PBMCs and tumor biopsies, with a significant expansion of circulating γ9δ2 T cells, and an increase in γ9δ2 T cells in the tumor biopsies at Day 28, considered key PD endpoints.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| On-going throughout the duration of the study |
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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 | 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 |
| second clinical trial with ICT01 |
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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.8.3 |
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 | 10 |
| 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 Kingdom |
| Germany |
| Spain |
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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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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