| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Oligometastatic solid tumors. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Oligometastatic solid tumors. |
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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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029522 |
| E.1.2 | Term | Non-small cell lung cancer stage IV |
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10059515 |
| E.1.2 | Term | Non-small cell lung cancer 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10066490 |
| E.1.2 | Term | Progression of non-small cell lung cancer |
| 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 | LLT |
| E.1.2 | Classification code | 10049280 |
| E.1.2 | Term | Solid tumour |
| 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 assess the therapeutic efficacy and toxicity of SBRT in combination with systemic PD-1 blockade and intratumoral PD-L1/CTLA-4 inhibition plus intratumoral administration of CD1c (BDCA-1)+/ CD141 (BDCA-3)+ myDC in patients with oligometastatic solid tumors. |
|
| E.2.2 | Secondary objectives of the trial |
• Safety
• Feasibility
• Objective response rate (ORR) by iRECIST
• Response of injected and non-injected tumor site
• Duration of response
• Progression-free survival (PFS)
• Overall survival (OS) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Subject has provided written informed consent prior to initiation of any study-specific activities/procedures.
• Male or female age ≥ 18 years at the time of informed consent.
• All subjects must have histologically confirmed advanced solid tumors that cannot be completely surgically resected
• All subjects must have received prior pembrolizumab or nivolumab (with or without cytotoxic chemotherapy or other additional drugs) and fail to respond to this treatment (patients must be documented with stable or progression of disease as their best response to this first-line therapy).
• "Oligometastatic” disease defined by a number of metastatic sites 7
• ECOG performance status of 0 or 1
• Patients need to have ≥ 1 metastatic lesion (≥ 10 mm in longest diameter) that can be safely injected by ultrasound-/ CT-guidance, by endo-bronchial ultrasound (EBUS) or even clinically. The lesion should also be amenable for safe biopsy.
• Injectable metastasis need(s) to be eligible for SBRT
• Adequate organ function determined within 14 days prior to enrollment
• Female subject of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to enrollment. If urine pregnancy test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• Subject has a tumor sample (a representative archival tissue sample obtained 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.
• Subjects should have adequate vascular access to undergo a leukapheresis
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| E.4 | Principal exclusion criteria |
•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 study treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids >8 mg/day of methylprednisone or equivalent. The exception does not include leptomeningeal metastasis which is excluded regardless of clinical condition.
•History or evidence of active autoimmune disease that requires systemic treatment Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
•History or evidence of immunodeficiency states (eg, hereditary immune deficiency, organ transplant, or leukemia)
•History of serious immune related adverse event during treatment with pembrolizumab in first-line
•History of other malignancy within the past 5 years of enrollment
* Prior treatment with immune-checkpoint inhibitors (including but not restricted to PD-1, PD-L1 and CTLA-4 blocking mAb) 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.
Subjects should not have ongoing grade 3 or 4 immune-related or chemotherapy-related adverse events.
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
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
•Other investigational procedures while participating in this study are excluded.
•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
•Evidence of clinically significant immunosuppression
•Known human immunodeficiency virus (HIV) disease
•Known acute or chronic hepatitis B or hepatitis C infection
•Known syphilis infection
•Female subject is pregnant or breast-feeding, or planning to become pregnant during study treatment and through 6 months after the last dose of study treatment
•Female subject of childbearing potential who is unwilling to use acceptable method(s) of effective contraception during study treatment and through 6 months after the last dose of study treatmentPostmenopausal (therapy. In the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.)
Male subject who is unwilling to use acceptable method of effective contraception during trial participation and through 6 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 azoospermia (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.
•Subject has known sensitivity to any of the products or components to be administered during dosing.
•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
•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 physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion.
•Is or has an immediate family member (eg, 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.
•Sexually active subject who is unwilling to use a barrier method (male or female condom) to avoid potential study drug transmission during sexual contact during and within 6 months after study treatment.
•Has undergone prior allogeneic hematopoietic stem cell transplantation within the last 5 years. (Subjects who have had a transplant greater than 5 years ago are eligible as long as there are no symptoms of Graft versus Host Disease.)
•Has a known history of active tuberculosis.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1-year progression free survival (PFS) rate following randomization. Adverse events occurring in patients treated in this phase II clinical trial will be collected on a continuous basis and monitored. Frequency and severity (graded according to the CTCAEEv4) will be reported descriptively |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1 year PFS: 1 year, AE monitoring: on a continuous basis |
|
| E.5.2 | Secondary end point(s) |
• Document the safety of intratumoral injection of autologous CD1c (BDCA-1)+CD141 (BDCA-3)+ myDC (isolated from PBMC) plus avelumab (an anti-PD-L1 IgG1 mAb) and ipilimumab (an anti-CTLA-4 IgG1 mAb) after hypofractionated SBRT in combination with IV administration of nivolumab (an anti-PD1 IgG4 mAb).
• Percentage of study patients that can receive the planned combination therapy
• The proportion of patients who have a partial or complete response to therapy
• Occurrence of abscopal responses (reported descriptively)
• Duration of response of CD1c (BDCA-1)+CD141 (BDCA-3)+ myDC, avelumab and ipilimumab injected and non-injected metastases (reported descriptively)
• Time from first study treatment administration to progression of disease according to RECISTv1.1 and iRECIST including landmark 6- and 12 months and median PFS
• Time from first first study treatment administration to death, including landmark 6- and 12 months and median OS |
|
| 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 | Yes |
| 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 | Yes |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| 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
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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 | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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