| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with injectable metastases from histologically confirmed solid tumors who have failed standard-of-care life prolonging therapeutic options will be invited to participate in this clinical trial. |
| Advanced solid tumors, progressive after standard of care. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Gevorderde solide tumoren, progressief na standaard behandeling |
| Patients with injectable metastases from solid tumors who have failed standard-of-care life prolonging therapeutic options will be invited to participate in this clinical trial. |
|
| 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 | 10007050 |
| E.1.2 | Term | Cancer |
| 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 |
To document the safety of intratumoral injection of autologous CD1c (BDCA-1)+ / CD141 (BDCA-3)+ myDC co-product (isolated from PBMC) plus AS01, and ipilimumab (anti-CTLA-4 IgG1 mAb) in combination with IV administration of nivolumab (anti-PD1 IgG4 mAb).
To assess the therapeutic efficacy and toxicity of the AS01B adjuvants in combination with systemic
PD-1 blockade and intratumoral CTLA-4 inhibition plus intratumoral administration of CD1c
(BDCA-1)+ / CD141 (BDCA-3)+ myDC co-product in patients with advanced melanoma |
|
| E.2.2 | Secondary objectives of the trial |
Feasibility
Treatment disposition
Anti-tumor activity
Duration of Response (DOR)
Progression free survival (PFS)
Overall survival (OS) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1)Subject has provided informed consent prior to initiation of any study-specific activities/procedures.
2)Male or female age ≥ 18 years at the time of informed consent
3)All subjects must have histologically confirmed advanced cancer that cannot be completely surgically resected and have failed all standard curative and life prolonging therapy.
4)All subjects must have non-visceral metastatic disease localizations that are amenable to intra-tumor injection by clinical and ultrasound (US) guidance. These metastases should be amenable to a safe post-injection biopsy (partial or complete).
5)ECOG performance status of 0 or 1
6)Candidate for intralesional therapy defined as either one of the following:
a)At least 1 injectable cutaneous, subcutaneous, or solid tumor lesion ≥ 10 mm in longest diameter
b)Multiple injectable solid tumor lesions that in aggregate have a longest diameter of ≥ 10 mm injectable disease
7)Adequate organ function determined within 28 days prior to enrollment, defined as follows:
a)Hematological
i)Absolute neutrophil count ≥ 1500/mm3 (1.5x109/L)
ii)Platelet count: ≥ 75.000/mm3 (7.5x109/L)
iii)Hemoglobin: ≥ 8 g/dL (without need for hematopoietic growth factor or transfusion support)
b)Renal
i)Serum creatinine: 1.5 x upper limit of normal (ULN), OR 24-hour creatinine clearance ≥ 60 mL/min for subject with creatinine levels > 1.5 x ULN. (Note: Creatinine clearance need not be determined if the baseline serum creatinine is within normal limits. Creatinine clearance should be calculated per institutional standard).
c)Hepatic
i)Serum bilirubin: 1.5 x ULN OR direct bilirubin ≤ ULN for a subject with total bilirubin level > 1.5 x ULN
ii)Aspartate aminotransferase (AST): 2.5 x ULN OR ≤ 5 x ULN for subject with liver metastases
iii)Alanine aminotransferase (ALT): 2.5 x ULN OR ≤ 5 x ULN for subject with liver metastases
d)Coagulation
i)International normalization ratio (INR) or prothrombin time (PT): 1.5 x ULN unless the subject is receiving anticoagulant therapy as long as PT and partial thromboplastin time (PTT)/ activated PTT (aPTT) is within therapeutic range of intended use of anticoagulants
ii)PTT or aPTT: 1.5 x ULN unless the subject is receiving anticoagulant therapyas long as PT and PTT/aPTT is within therapeutic range of intended use of anticoagulants
8)Female subject of childbearing potential should have a negative serum pregnancy test within 72 hours prior to enrollment.
9)Subject has a tumor sample (archival sample obtained within 3 months prior to study participation or newly obtained biopsy). Subject must submit the tumor sample during screening. Subjects with a non-evaluable archival sample may obtain a new biopsy and subjects with a non-evaluable newly obtained biopsy may undergo re-biopsy at the discretion of the investigator.
10)Adequate vascular access to undergo a leukapheresis.
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|
| E.4 | Principal exclusion criteria |
1)Known active central nervous system (CNS) metastases. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids >10 mg/day of prednisone or equivalent. The exception does not include leptomeningeal metastasis which is excluded regardless of clinical stability.
2)History or evidence of active autoimmune disease that requires systemic treatment (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
3)History or evidence of cancer associated with immunodeficiency states (e.g., hereditary immune deficiency, organ transplant, or leukemia)
4)History of other malignancy within the past 5 years with exceptions
2)Prior treatment of another tumor vaccine
3)Receive live vaccine within 28 days prior to enrollment
4)Prior chemotherapy, radiotherapy, biological cancer therapy, targeted therapy, or major surgery within 28 days prior to enrollment or has not recovered to CTCAE grade 1 or better from adverse event due to cancer therapy administered more than 28 days prior to enrollment.
5)Currently receiving treatment in another investigational device or drug study, or less than 28 days since ending treatment on another investigational device or drug study
6)Expected to require other cancer therapy while on study with the exception of local radiation treatment to the site of bone and other metastasis for palliative pain management
7)Other investigational procedures while participating in this study are excluded.
8)History or evidence of symptomatic autoimmune pneumonitis, glomerulonephritis, vasculitis, or other symptomatic autoimmune disease, or active autoimmune disease or syndrome that has required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs) except vitiligo or resolved childhood asthma/atopy. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
9)Evidence of clinically significant immunosuppression
10)Known human immunodeficiency virus (HIV) disease
11)Known acute or chronic hepatitis B or hepatitis C infection
12)Known syphilis infection
13)Female subject is pregnant or breast-feeding, or planning to become pregnant during study treatment and through 5 months after the last dose of study treatment
14)Female subject of childbearing potential who is unwilling to use acceptable method(s) of effective contraception during study treatment and through 5 months after the last dose of study treatment.
15)Male subject who is unwilling to use acceptable method of effective contraception during trial participation and through 5 months after the last dose of study treatment. For this trial, male subjects will be considered to be of non-reproductive potential if they have azoöspermia (whether due to having had a vasectomy or due to an underlying medical condition). Note: Acceptable methods of effective contraception are defined in the informed consent form.
16)Subject has known sensitivity to any of the products or components to be administered during dosing
17)Subject likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures to the best of the subject and investigator’s knowledge
18)History or evidence of psychiatric, substance abuse, or any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion
19)Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling, or child) who is investigational site or sponsor staff directly involved in this trial, unless prospective institutional review board (IRB)/independent ethics committee (IEC) approval (by chair or designee) is given allowing exception to this criterion for a specific subject
20)Sexually active subject who is unwilling to use a barrier method (male or female condom) to avoid potential viral transmission during sexual contact during and within 30 days after treatment
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Adverse events occurring in patients treated in this phase I clinical trial (collected on a continuous basis). Type, frequency and severity (graded according to the CTCAEv5.0) will be reported descriptively.
1-year progression free survival (PFS) rate following randomization. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| continues throughout the study |
|
| E.5.2 | Secondary end point(s) |
•Percentage of study patients that can receive the planned CD1c (BDCA-1)+ / CD141 (BDCA-3)+ myDC intratumoral injection.
•Number/volume of administered CD1c (BDCA-1)+ / CD141 (BDCA-3)+ myDC
•Administered dose of AS01, ipilimumab, and nivolumab
•Tumor response (ORR) according to RECISTv1.1 and iRECIST
•Tumor response and duration of response of CD1c (BDCA-1)+ / CD141 (BDCA-3)+ myDC,AS01 and ipilimumab injected and non-injected metastases (reported descriptively)
•Duration of response of CD1c (BDCA-1)+ / CD141 (BDCA-3)+ myDC, AS01B and pilimumab in injected and noninjected metastases (reported descriptively)
•Time from first study treatment administration to progression of disease according to RECISTv1.1 and iRECIST (and possibly itRECIST)
•Time from first study treatment administration to death
•Immunohistochemical analysis (CD3, CD8, CD4, PD-L1), multiplexed immunofluorescent imaging, and RNA-expression profiling (NanoString PanCancer IO 360 gene expression panel) of repetitive on-treatment tissue biopsies of injected metastases
•T-cell receptor repertoire in metastases assessed by ImmunoSEQ analysis
•Peripheral blood differential white blood cell counts
•Immunocytochemical differential cell counts (incl. CD3+, CD4+ and CD8+ lymphocytes)
•T-cell receptor repertoire assessed by ImmunoSEQ analysis
•Flow cytometric analysis of effector/naïve/memory T cells
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| continues throughout the study and at the end of the study |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| 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) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| 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 | Yes |
| 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 | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
| Confirmed progression of disease, unacceptable toxicity, the patients refusal to continue the study or death of the patient. |
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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 | 1 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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