A randomized phase II clinical trial on intratumoral AS01B/ipilimumab plus intravenous nivolumab with or without autologous CD1c(BDCA-1)+ / CD141(BDCA-3)+ myeloid dendritic cells.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

UZ Brussel

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Not possible to specify

Trial duration

8 Jan 2018 → ongoing

Decision date (initial)

2024-09-16

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-517094-24-00

EudraCT number

2017-003280-35

ClinicalTrials.gov

NCT03707808

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

To assess the therapeutic efficacy and toxicity of the AS01B adjuvants in combination with systemic PD-1 blockade and intratumoral CTLA-4 inhibition plus intratumoraladministration of CD1c(BDCA-1)+ / CD141(BDCA-3)+ myDC co-product in patients with advanced melanoma.

Secondary objectives 6

1. Feasability
2. Treatment disposition
3. Anti-tumor activity
4. Duration of response (DOR)
5. Progression-free survival (PFS)
6. Overall survival

Conditions and MedDRA coding

Solid tumors

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

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, ultrasound (US), CT-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 therapy as ong 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.

Exclusion criteria 25

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 the following exceptions: i) Malignancy treated with curative intent and with no known active disease present and has not received chemotherapy for > 5 years before enrollment and felt to be at low risk for recurrence by the treating physician ii) Adequately treated non-melanoma skin cancer without evidence of disease at the time of enrollment iii) Adequately treated cervical carcinoma in situ without evidence of disease at the time of enrollment iv) Adequately treated breast ductal carcinoma in situ without evidence of disease at the time of enrollment v) Prostatic intraepithelial neoplasia without evidence of prostate cancer at the time of enrollment vi) Adequately treated superficial or in-situ carcinoma of the bladder without evidence of disease at the time of enrollment
5. Prior treatment of another tumor vaccine
6. Receive live vaccine within 28 days prior to enrollment
7. 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.
8. 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
9. 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
10. Other investigational procedures while participating in this study are excluded.
11. 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.
12. Evidence of clinically significant immunosuppression such as the following: i) Diagnosis of immunodeficiency ii) Concurrent opportunistic infection iii) Receiving systemic immunosuppressive therapy (> 2 weeks) or within 7 days prior to the first dose of study treatment, including oral steroid doses > 10 mg/day of prednisone or equivalent except for management of adverse events and central nervous system (CNS) metastases during the course of the study. Subjects that require intermittent use of bronchodilators or local steroid injection will not be excluded from the study.
13. Known human immunodeficiency virus (HIV) disease
14. Known acute or chronic hepatitis B or hepatitis C infection
15. Known syphilis infection
16. 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
17. 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. Note: Women not of childbearing potential are defined as: a) Postmenopausal (defined as at least 12 months with no menses without an alternative medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. In the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.) OR b) Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; OR c) Has a congenital or acquired condition that prevents childbearing. Note: Acceptable methods of effective contraception are defined in the informed consent form.
18. 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 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.
19. Subject has known sensitivity to any of the products or components to be administered during dosing
20. 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
21. 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
22. 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
23. 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
24. 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.)
25. Has a known history of active Bacillus tuberculosis

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. 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 CTCAEv5) will be reported descriptively
2. Type, frequency and severity (graded according to the CTCAEv5.0) of intratumoral injection of CD1c (BDCA-1)+ / CD141 (BDCA-3)+ myDC's with IT AS01B and IT ipilimumab in combination with IV nivolumab

Secondary endpoints 6

1. Percentage of study patients that can receive the planned CD1c (BDCA-1)+ / CD141 (BDCA-3)+ myDC intratumoral injection.
2. Number/volume of administered CD1c (BDCA-1)+ / CD141 (BDCA-3)+ myDC administered dose of AS01, ipilimumab, and nivolumab
3. 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)
4. Duration of response of CD1c  (BDCA-1)+ / CD141 (BDCA-3)+  myDC, AS01B and  ipilimumab in injected and noninjected metastases (reported  descriptively)
5. Time from first study treatment administration to progression of disease according to RECISTv1.1 and iRECIST (and possibly itRECIST)
6. Time from first study treatment administration to death

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

UZ Brussel

Sponsor organisation

UZ Brussel

Address

Laarbeeklaan 101

City

Jette

Postcode

1090

Country

Belgium

Scientific contact point

Organisation

UZ Brussel

Contact name

Evelien Vandeurzen

Public contact point

Organisation

UZ Brussel

Contact name

Evelien Vandeurzen

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 8 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications