Pathologic and radiographic responses in a window of opportunity for durvalumab plus metformin trial for squamous cell carcinoma of the head and neck (HNSCC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 6068-6068
Author(s):  
Joseph M. Curry ◽  
Angela Alnemri ◽  
Brian Swendseid ◽  
Uche Nwagu ◽  
David M. Cognetti ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Immune Cell ◽  
Synergistic Effects ◽  
Phase 1 ◽  
Cell Polarization ◽  
Trial Participation ◽  
Window Of Opportunity ◽  
Radiographic Disease ◽  
Tumor Distribution ◽  
Stage Ivb

6068 Background: Durvalumab is a human monoclonal IgG1 antibody directed against programmed death-ligand 1 (PD-L1). PD-1/PD-L1 immune checkpoint inhibition (ICI) shows promise in HNSCC, but durable responses have been seen in only a fraction of patients. Metformin, a biguanide oral anti-hyperglycemic, has shown promise in altering immunity within the tumor microenvironment (TME) towards a stronger anti-tumor distribution of immune cells. We aimed to investigate the combined effect of metformin and durvalumab in patients with HNSCC. Methods: This was a single-center prospective phase 1, window of opportunity clinical trial in which previously untreated patients with any stage resectable HNSCC were randomized 3:1 to durvalumab + metformin (Arm A) or durvalumab alone (Arm B) during a four-week period between diagnosis and surgical resection. Six patients were included in a safety lead-in of durvalumab and metformin and an additional 32 patients were randomized. The primary endpoint was immune cell polarization. Here we report pathologic and radiographic effect. Pathologic effect was graded independently by two pathologists. Radiographic effect was evaluated using the immune-related Response Criteria (irRC). Results: Thirty-eight patients were enrolled (29 Arm A, 9 Arm B). Three patients withdrew consent prior to intervention (2 Arm A, 1 Arm B) and were excluded from analysis. AJCC 8th edition staging was as follows: Stage I (n = 21), Stage II (n = 2), Stage III (n = 3), Stage IVa (n = 6), Stage IVb (n = 3). Primary tumor sites included the oropharynx (n = 20, all p16+), oral cavity (n = 11), larynx (n = 2), maxillary sinus (n = 1), and unknown (n = 1). Pathologic effect was observed in 55% (18/33) of evaluable patients: 60% in Arm A vs 37.5% in Arm B (p = 0.418). 40% of patients with involved lymph nodes had discordance of pathologic effect at the primary site versus lymph node. Radiographic response based on irRC among 30 evaluable patients included 1 CR, 1 PR, 24 SD, and 4 PD. There was a significant correlation between pathologic effect and radiographic disease control, defined as CR, PR, and SD (p = 0.021), but no correlation when looking only at radiographic responders (p = 0.925). No patients experienced Grade 3–4 treatment or immune-related adverse events or a delay in surgery due to trial participation. All patients remained resectable. Conclusions: Our data demonstrate that the study intervention was well-tolerated in HNSCC patients. There was a trend towards an increased proportion of pathologic responders in the group receiving metformin. Additional studies targeting the TME are needed to further elucidate whether synergistic effects between metformin and durvalumab were seen in this patient cohort. Clinical trial information: NCT03618654.

Phase 1/2 trial of cirmtuzumab and ibrutinib: Planned analysis of phase 1 CLL cohorts.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 7527-7527 ◽  
Author(s):  
Michael Y. Choi ◽  
William G. Wierda ◽  
Hun Ju Lee ◽  
Dimitrios Tzachanis ◽  
Xen Ianopulos ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Synergistic Effects ◽  
Phase 1 ◽  
Complete Response ◽  
Mantle Cell ◽  
Trisomy 12 ◽  
Previously Treated ◽  
Grade 3 ◽  
Dose Levels ◽  
Current Clinical Trial

7527 Background: Cirmtuzumab (C) is a humanized mAb that binds ROR1 and blocks Wnt5a from binding and activating ROR1 on CLL and mantle cell lymphoma (MCL); C does not bind normal adult tissues. A phase 1 trial of C showed excellent safety and inhibition of Wnt5a-ROR1 signaling. Ibrutinib (Ibr) does not inhibit the ROR1 pathway, and C+Ibr exert synergistic effects in CLL and MCL. The current clinical trial combines C+Ibr for patients (pts) with CLL and MCL. A planned analysis of the phase 1 CLL portion is presented. Methods: Eligible pts had CLL needing treatment according to iwCLL guidelines. C was given at 2, 4, 8, or 16 mg/kg q 2 wk for 8 wk, then q 28 d to 52 wk. Ibr 420 mg PO daily was started on d 28. Results: 3 pts were treated at each C dose level with age 57-86; 75% were previously treated (median 2); 3 pts had del(11q), 3 had trisomy 12, and 6 pts had unmutated IGVH genes. There were no discontinuations for toxicity and no dose limiting toxicities. Treatment with C alone and combined with Ibr was well-tolerated. One SAE occurred with C monotherapy (hospitalization for tonsillitis). Adverse events on C+Ibr were consistent with the known Ibr safety profile, with one grade 3 hyperkalemia and 1 atrial fibrillation event. All other AEs were grade 1 or 2. The overall response rate after 16-48 weeks of treatment was 67% with 1 confirmed complete response (CR) with no morphologic evidence of CLL in the marrow, 1 clinical CR, 6 partial responses (PR) and 4 stable disease. No patient had progressive disease. The typical redistributive lymphocytosis seen with Ibr was blunted, with only a 50% mean rise in ALC, rapidly returning to baseline. PRs were observed in all C dose levels. Conclusions: The combination of C+Ibr is well-tolerated and effective. CRs were observed in 2 cases, a result that would be highly unusual with Ibr monotherapy in CLL. Based on these findings, Cirm 600 mg was selected as the RP2D for the randomized phase 2 portion of this protocol, which will prospectively compare the complete response rates between C+Ibr and Ibr alone. Clinical trial information: NCT03420183.

A phase I, first-in-human clinical trial of the GDF-15 neutralizing antibody CTL-002 in subjects with advanced-stage solid tumors (ACRONYM: GDFATHER).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS2658-TPS2658
Author(s):  
Ignacio Melero ◽  
Emiliano Calvo ◽  
Reinhard Dummer ◽  
Elena Garralda ◽  
Martin H. Schuler ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cell ◽  
Solid Tumors ◽  
Tumor Tissue ◽  
Immune Cell ◽  
Phase 1 ◽  
Neutralizing Antibody ◽  
Advanced Stage ◽  
Open Label ◽  
Effector T Cell

TPS2658 Background: Growth and differentiation factor 15 (GDF-15) is a TGF-β superfamily member physiologically expressed mainly in placenta and linked to feto-maternal tolerance. Under pathophysiologic conditions, prevention of excessive immune cell infiltration during tissue damage and cachexia induction have been ascribed to GDF-15. A recent study [Haake et al. AACR2020; Abstract #5597] elucidated a mechanism by which GDF-15 inhibits LFA-1 activation on CD8+ T cells, thus interfering with effector T cell recruitment to tissues. Importantly, several cancer entities secrete high levels of GDF-15, correlating with poor prognosis and reduced overall survival [reviewed in Front Immunol 2020 May 19;11:951]. To block this effect the GDF-15 neutralizing antibody CTL-002 was generated. In preclinical models CTL-002 demonstrated potent effector T cell shifting into tumor tissue by neutralizing GDF-15. Methods: This is a phase 1, first-in-human (FIH), two-part, open-label clinical trial of intravenous (IV) administration of CTL-002 given as monotherapy and in combination with an anti-PD-1 antibody in subjects with advanced-stage, relapsed/refractory solid tumors who relapsed post or were refractory to a prior anti-PD-1/PD-L1 therapy. Eligible subjects have exhausted all available approved standard treatments. Further key eligibility criteria include having received at least one prior anti-PD1/-PD-L1 treatment and having relapsed on or after it or having been refractory to it, and presenting with a biopsy-accessible tumor for serial biopsy taking. The trial is termed GDFATHER, for “GDF-15 Antibody-mediaTed Effector cell Relocation”. Main endpoints are safety of CTL-002 monotherapy and CTL-002 combination with an anti-PD-1 antibody, pharmacokinetics, pharmacodynamics (e.g. degree of GDF-15 neutralization achieved and change in immune-cell number and composition in the tumor tissue) as well as preliminary clinical efficacy (tumor mass reduction; anticachexia effect) In part A of the trial (dose escalation) up to 24 subjects will receive escalating doses of CTL-002 IV (0.3 – 20 mg/kg) in a „mono-followed-by-combination“-design with CTL-002 given as monotherapy and followed by combination with an anti-PD-1 checkpoint inhibitor. In part B (expansion) up to 5 cohorts with up to 25 subjects per cohort with defined tumor entities expected to be GDF-15 dependent will be treated to determine the recommended phase 2 dose (RP2D) and further evaluate safety and preliminary efficacy of CTL-002 monotherapy and the combination. The study was initiated in December 2020 and enrolled the first patient on Dec 09, 2020. Cohort 1 has been completed without DLT and enrollment for cohort 2 began in February 2021. Clinical trial information: NCT04725474.

Lyc-55716: A novel small-molecule RORγ agonist immuno-oncology agent: Rationale for tumor selection and clinical evaluation of gastric and esophageal carcinoma in phase 2a expansion.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 67-67 ◽  
Author(s):  
Garry Alan Weems ◽  
Xiao Hu ◽  
Xikui Liu ◽  
Hongxiu Li ◽  
Madhumita Bogdan ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
Esophageal Carcinoma ◽  
Immune Cell ◽  
Phase 1 ◽  
The Cancer Genome Atlas ◽  
Orphan Receptor ◽  
Signature Genes ◽  
Low Levels ◽  
Public Datasets

67 Background: Type 17 effector T cell differentiation and function are regulated by the master transcription factor retinoic acid receptor–related orphan receptor γt (RORγ). Synthetic RORγ agonists, which modulate immune cell gene expression to enhance effector functions and decrease Treg and checkpoint pathways, have shown promise as mono- and combination therapy in syngeneic tumor models. Translational and bioinformatics assessments were performed during Phase 1 testing of the investigational RORγ agonist LYC-55716 to support inclusion of patients with gastric carcinoma (GC) and esophageal carcinoma (EC) in a Phase 2a expansion of clinical trial LYC-55716-1001 (NCT02929862). Methods: Transcriptional profiling of murine and human T cells treated ± RORγ agonists identified a gene signature. Using The Cancer Genome Atlas (TCGA), and other public datasets, data on GC and EC patients were evaluated to determine: (a) RORγ and RORγ-inducing cytokine expression; (b) signature genes associated with RORγ biology, surrogate biomarkers for endogenous RORγ ligands, and correlations with prognosis; (c) tumor microenvironment (TME) immune profiles. Results: Expression: In TCGA RNA sequencing data analysis, 50%-70% of GC and EC samples expressed moderate to high levels of RORγ, indicating infiltration of Type 17 T cells into the tumors. Furthermore, genes that support expression of RORγ were highly expressed in ~75% of GC and EC tumors. Biology: TCGA data showed that GC and EC tumors express low levels of sterol efflux genes, suggesting low levels of endogenous agonists in the TME. In analysis of public datasets, expression of the RORγ target gene IL17A correlated with a favorable prognosis for EC. In addition, some of the other RORγ signature genes also correlated with good prognosis in GC and EC. Immune profile: TCGA showed infiltration of T cells and a high mutational burden in GC and EC, which are positively associated with efficacy of immunotherapy. Conclusions: Bioinformatics assessments of RORγ expression, biology, and tumor immune profiles support the inclusion of GC and EC patients in an ongoing Phase 2 clinical trial of LYC-55716.

scholarly journals Who Needs What? Perceptions of Patients and Caregivers in Oncology Phase 1 Trials

2019 ◽  
Vol 7 (1) ◽  
pp. 27-33 ◽  
Author(s):  
Victoria Rezash ◽  
Janice Reed ◽  
Barbara Gedeon ◽  
Eric Parsons ◽  
Sandra Siedlecki ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Phase 1 ◽  
Trial Participation ◽  
Clinical Trial Participation ◽  
Oncology Clinical Trial ◽  
Oncology Clinical Trials ◽  
Vulnerable Patient ◽  
Additional Support

Background: The study design and nature of oncology phase 1 clinical trials create a uniquely vulnerable patient population yet little research has been conducted to identify the added burden these trials create for both cancer patients and their caregiver(s). Objective: Examining the perceptions and needs of patients and their caregivers participating in phase 1 oncology clinical trials, the investigators tested the hypothesis that the caregiver will exhibit a higher level of burden and/or distress than the patient. Method: A mixed-methods exploratory process utilizing patient and caregiver interviews and quality-of-life questionnaires was used to assess the psychosocial burdens associated with oncology clinical trial participation. A qualitative and quantitative analysis of the responses were 8 performed. Result: Both patients and caregivers reported similar themes identifying the burdens and benefits related to phase 1 clinical trial participation. However, the caregivers’ expressed burden exceeded that of the patients’ validating the study’s hypothesis. Conclusion: The need for ongoing additional support services for not only the patient but also the caregiver was identified.

CTIM-15. FIRST-IN-HUMAN PHASE 1 STUDY OF CD200 ACTIVATION RECEPTOR-LIGAND (CD200AR-L) AND ALLOGENEIC TUMOR LYSATE VACCINE IMMUNOTHERAPY FOR RECURRENT GLIOBLASTOMA: INITIAL RESULTS FROM AN ONGOING CLINICAL TRIAL

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi52-vi53
Author(s):  
Elizabeth Neil ◽  
Anne Eaton ◽  
Shannon Lunn ◽  
Kristen Nelson ◽  
Emily Greengard ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
Disease Progression ◽  
Natural Killer ◽  
Dose Level ◽  
Phase 1 ◽  
Radiographic Disease ◽  
Level 1 ◽  
Dose Limiting Toxicity ◽  
Grade Iii

Abstract BACKGROUND Poor efficacy and adverse events limit the use of immunotherapy in the treatment of glioblastoma. CD200AR-L, a novel immunotherapy targeting multiple checkpoints with a single peptide inhibitory ligand, activates the immune system by downregulating CD200-inhibitory receptor, PD-1/PD-L1, and CTLA-4. METHODS Single-center, first-in-human, dose-escalation phase 1 clinical trial (NCT04642937) utilizing a 3 + 3 design initiated accrual in 12/2020 at dose level-1; CD200AR-L 3.75micrograms/kg/dose administered on days 1 and 2 by intradermal injection after topical imiquimod. On day 2, a fixed dose of an allogeneic vaccine is also injected intradermally. Induction Phase consists of this injection series weekly for 4 weeks with monitoring for dose-limiting toxicity through day 28. RESULTS Between 12/2020 to 3/2021, 6 patients were enrolled on dose level-1; aged 37-65 years, 4 men, all with KPS >/= 80, and 3 patients on daily dexamethasone (4mg (n=2), 2mg (n=1)). Five were at first recurrence, 1 at second and 5 had cancers MGMT-promoter unmethylated. All completed the 4 weeks of induction. One dose-limiting toxicity of a grade-III encephalopathy was observed. Non-dose-limiting grade-III toxicities included, lymphopenia (n=1) and immunotherapy-related intracranial edema (IrICE) (n=2). IrICE symptoms were temporarily mitigated with ‘bevacizumab rescue protocol.’ No patients had local injection site reactions. Three patients are off study for radiographic disease progression confirmed on pathology (n=1) and radiographic disease progression with progressive neurological decline (n=2). Completed investigational hematologic immune monitoring for 4/6 patients revealed, that between weeks 2 and 4 post-vaccination, evidence of immune stimulation with an increase in CD4/8 T-cells, natural killer, and natural killer T-cells. There was also a reduction in immunosuppressants noted by a decrease in PD-1/PD-L1 and CTLA-4 expression on CD4/8 T-cells, CD14, CD11c, and myeloid-derived suppressor cells. CONCLUSION Initial dosing of CD200AR-L was well tolerated with early positive signal of immunological effect. Enrollment continues, now at dose level-2; CD200AR-L at 5micrograms/kg/dose.

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