Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Prostatic Neoplasms

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

All Drugs and Chemicals

Antineoplastic Agents

Antibodies

Antibodies, Monoclonal

Abiraterone Acetate

Immunoglobulins

Enzyme Inhibitors

Hormones

Hormone Antagonists

Cytochrome P-450 Enzyme Inhibitors

Increasing doses of tildrakizumab in combination with a fixed dose of abiraterone to establish the recommended phase II dose in patients with metastatic castration resistant prostate cancer..

The Phase II part of the study will evaluate the recommended phase II dose identified in Phase I of the study in patients with metastatic castration resistant prostate cancer.

Tildrakizumab will be supplied in single-use 100 mg/mL glass vials intended for IV infusion.

Tildrakizumab

Johann De Bono, MD

The purpose of this study is to find out the side effects and safety of a combination of the anti-IL23 targeting monoclonal antibody tildrakizumab in combination with abiraterone acetate in men with metastatic castration resistant prostate cancer and to determine the most appropriate dose of this combination. In the Phase I part of this study small groups of patients will be treated with increasing doses of tildrakizumab in combination with a fixed dose of abiraterone acetate (500mg once daily). Once Phase I has been completed the combination with the optimum safety and pharmacokinetic/pharmacodynamic profile will be taken forward to the Phase II part of the study. The Phase II part of the study will evaluate the optimized dose/schedule identified in Phase I of the study in patients with metastatic castration resistant prostate cancer.

The trial will be divided into 2 parts: Phase I and Phase II.

The Phase I study will adopt a Bayesian Continual Reassessment Method. Patients will receive single-agent abiraterone run-in of 500 mg orally, once daily (continuous dosing) along with prednisolone at 5 mg BD until PSA progression on abiraterone monotherapy is confirmed. This run-in will not be required if patients have been treated with abiraterone in the previous 6 months. Upon confirmation of PSA progression, tildrakizumab IV will be started and given once every 4-weeks in combination with the fixed dose abiraterone (and prednisolone). The starting dose of tildrakizumab will be 100mg, with single dose escalations to 300mg and 600mg to determine the RP2D to take forward to the Phase II study. Depending on the number of responses observed, dose levels that are deemed tolerable may be expanded to up to a total of 10 patients who are evaluable for response.

The Phase II study will employ a two-stage Minimax design, recruiting up to 25 patients. During the first stage, 15 evaluable patients will be enrolled and followed for a minimum of 2 cycles each. If there are one or more responses confirmed at least 4-weeks later, an additional 10 evaluable patients will be recruited. If 4 or more responses are seen in the 25 patients evaluable for response, the combination will be deemed successful, warranting further evaluation in subsequent phases of testing. In the phase II study, patients will start taking 500mg abiraterone as an oral tablet once daily along with 5mg of prednisolone twice daily until PSA progression on abiraterone monotherapy is confirmed. This run-in will not be required if patients have been treated with abiraterone in the previous 6 months. Upon confirmation of PSA progression, the tildrakizumab will be given as an intravenous infusion at the dose established in the Phase I safety part of the study in combination with the abiraterone (and prednisolone) from combination Cycle 1 Day 1 onwards.

Abiraterone Acetate in Combination With Tildrakizumab

ACTION: Phase I/II Trial of Abiraterone Acetate in Combination With Tildrakizumab (Anti-IL23 Targeting Monoclonal Antibody) in Men With Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Deregulation, amongst others, of IL-23, STAT proteins, AR, AR splice variants.

Correlate anti-tumour activity of the combination of tildrakizumab and abiraterone with the detection of putative predictive biomarkers of response and resistance in archival tumours, paired fresh tumour biopsies, and plasma samples.

To determine a maximum tolerated dose (MTD) of tildrakizumab by establishing the dose at which the DLT rate is as close to the target DLT rate of 15% as possible, in combination with abiraterone at 500 mg OD with prednisolone at 5 mg bid, and is deemed to be tolerable by the Safety Review Committee. This will be the RP2D for tildrakizumab.

Antitumour activity will be defined by response rate on the basis of the following outcomes. If any of the following occur, patients will be considered to have responded:

* PSA decline ≥ 50% criteria confirmed 4-weeks or later and/or,
* Confirmed soft tissue objective response by RECIST (v1.1) in patients with measurable disease and/or,
* ONLY for patients with detectable circulating tumour cell (CTC) count of ≥ 5/7.5ml blood at baseline, conversion of CTC count to \<5/7.5ml blood nadir.

Measuring the impact of the downregulation of IL-23 signaling in tumour, also evaluating the downregulation of androgen receptor (AR), AR splice variants, and AR target genes.

Determine peak plasma concentration (Cmax) of tildrakizumab and abiraterone when dosed together.

Determine the terminal elimination half-life (T1⁄2) of tildrakizumab and abiraterone when dosed together.

Determine the area under the plasma concentration versus time curve (AUC) of tildrakizumab and abiraterone when dosed together.

Determine biomarkers of response, including but not limited to PTEN loss, MYC amplification, and intra-tumour MDSC counts, in tumour biopsies from responders and non-responders.

Response and progression will be determined using the same measures as that described for the primary objective of the Phase II study.

PFS will be measured from the date of addition of tildrakizumab to abiraterone to the date of progression as determined by radiological criteria (RECIST v 1.1, PCWG3 bone scan criteria) or unequivocal clinical progression necessitating drug discontinuation (e.g. worsening pain, spinal cord compression, need for other anticancer therapy).

OS will be measured from the date of addition of tildrakizumab to abiraterone to the date of death (whatever cause).

The time to PSA Progression will be measured from the date of addition of tildrakizumab to abiraterone.

The duration of PSA decline by ≥ 50%, where this is seen in responding patients.

The maximum PSA decline experienced per patient. This will be measured following the addition of tildrakizumab to abiraterone.

The maximum percentage of PSA decline experienced per patient. This will be measured following the addition of tildrakizumab to abiraterone.

Time to radiological progression (RECIST 1.1 \& PCWG3 Bone Scan criteria). Radiologic PFS (rPFS).

Measure the impact of the downregulation of IL-23 signaling in tumour, also evaluating the downregulation of androgen receptor (AR), AR splice variants, and AR target genes

Rate of CTC conversion from ≥ 5/7.5 ml blood to \< 5/7.5 ml

Causality and grading severity of each adverse event related to the tildrakizumab and abiraterone combination according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0

Sun Pharmaceutical Industries Limited

Institute of Cancer Research, United Kingdom

Blood and Lymph Conditions

Immune System Diseases

Rare Diseases

Hematologic Neoplasms

Graft vs Host Disease

Hematologic Diseases

Homologous Wasting Disease

Acute Graft Versus Host Disease

Interleukin-23

Tildrakizumab (IluymaTM) is a humanized monoclonal antibody that specifically binds to the IL-23p19 subunit of IL-23 to neutralize its function.

100 mg will be injected subcutaneously on Day -1, Day 28 ± 3, Day 112 ± 7, Day 196 ± 14, and Day 280 ± 14.

Lyndsey Runaas, MD

This is a phase 2 open-label trial designed to evaluate the efficacy of tildrakizumab in improving graft-versus-host disease (GVHD)-free relapse-free survival after myeloablative allogeneic hematopoietic cell transplantation (alloHCT) for hematologic malignancy.

Study Rationale: GVHD remains a major cause of morbidity and mortality following myeloablative conditioning (MAC) alloHCT. Proinflammatory cytokines play a central role in initiation and development of acute GVHD and as such, inhibition of these cytokines has been examined for both prevention and treatment of GVHD. Interleukin (IL)-23 is a proinflammatory cytokine which the investigators' lab has shown to have a unique and selective role in induction of colonic inflammation during acute GVHD and that this cytokine serves as a critical mediator linking conditioning regimen-induced mucosal injury and endotoxin lipopolysaccharide (LPS) translocation to subsequent proinflammatory cytokine production and GVHD-associated pathological damage. Moreover, additional studies have demonstrated that blocking the IL-23 signaling pathway has not abrogated the graft-versus-tumor effect. Tildrakizumab is a commercially available anti-IL-23 antibody FDA approved for the treatment of moderate to severe psoriasis with good tolerance. The investigators hypothesize that blocking IL-23, with tildrakizumab, will reduce GVHD rates for patients undergoing MAC alloHCT without having an impact on relapse rates, thus improving GVHD-free relapse-free survival (GRFS).

Tildrakizumab for Prevention of Acute Graft-Versus-Host Disease

A Phase II Trial of Tildrakizumab for Prevention of Acute Graft-Versus-Host Disease

Number of subjects experiencing any of grade III-IV acute GVHD, systemic therapy-requiring chronic GVHD, relapse, or death at 12 months

Number of subjects experiencing chronic GVHD defined by NIH Consensus criteria.

Number of subjects experiencing grades II-IV and III-IV acute GVHD will be determined at Day +100 and Day +180 post-HCT. Acute GVHD will be graded according to NIH Consensus criteria.

Number of subjects experiencing grades II-IV and III-IV acute GI GVHD will be determined at Day +100 and Day +180 post-HCT. This will be graded according to NIH Consensus criteria.

Number of subjects experiencing no neutrophil recovery to \> 500 cells/μL by Day 28 post-HCT.

Number of subjects experiencing initial neutrophil engraftment followed by subsequent decline in absolute neutrophil counts \<500 cells/μL, unresponsive to growth factor therapy, but cannot be explained by disease relapse or drugs.

The number of days to hematopoietic recovery will be assessed according to neutrophil count recovery after hematopoietic stem cell transplant (HSCT). Neutrophil recovery or engraftment is defined as achieving an absolute neutrophil count (ANC) ≥500/mm\^3 for three consecutive measurements on three different days. The first of the three days will be designated the day of neutrophil engraftment.

The number of days to hematopoietic recovery will be assessed according to platelet count recovery after HSCT. Platelet recovery is defined by either the first day of a sustained platelet count \>20,000/mm\^3 for three days with no platelet transfusion in the preceding seven days. The first day of sustained platelet count above these thresholds will be designated the day of platelet engraftment.

Number of subjects who die after alloHCT without experiencing a relapse.

The number of subjects who experience relapse. Relapse is defined by either morphological, cytogenetic or radiologic evidence of the pretransplant hematologic malignancy.

This will be measured in months. The event for this endpoint is relapse/progression or death. Patients who are alive and disease-free will be censored at last follow-up.

The time in months from the date of transplant to date of death from any cause or for surviving patients, to last follow-up. Patients who are alive and disease-free will be censored at last follow-up.

Number of subjects experiencing a grade ≥3 (CTCAE v5) viral, fungal and/or bacterial infections.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Abiraterone Acetate in Combination With Tildrakizumab	NCT04458311	Metastatic Cast...	Abiraterone Ace... Tildrakizumab	18 Years -	Institute of Cancer Research, United Kingdom
Tildrakizumab for Prevention of Acute Graft-Versus-Host Disease	NCT04112810	Hematologic Mal...	Tildrakizumab	18 Years -	Medical College of Wisconsin
Abiraterone Acetate in Combination With Tildrakizumab	NCT04458311	Metastatic Cast...	Abiraterone Ace... Tildrakizumab	18 Years -	Institute of Cancer Research, United Kingdom

Spots Global Cancer Trial Database for tildrakizumab