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  • 1
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    AIRPanc: A phase 2, open-label, multicenter, randomized study evaluating neoadjuvant therapy targeting the adenosine immunosuppressive pathway in combination with immune checkpoint blockade and radiation therapy in patients with advanced pancreatic ductal adenocarcinoma who are candidates for surgical resection.
    American Society of Clinical Oncology (ASCO) ; 2024
    In:  Journal of Clinical Oncology Vol. 42, No. 3_suppl ( 2024-01-20), p. TPS714-TPS714
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 42, No. 3_suppl ( 2024-01-20), p. TPS714-TPS714
    Abstract: TPS714 Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease for which immune checkpoint blockade (ICB) has not provided benefit, hypothesized to be due to the presence of an immunosuppressive tumor microenvironment (TME). Neoadjuvant multi-agent chemotherapy and stereotactic body radiation therapy (SBRT) may increase immunosuppression by elevating intratumoral levels of adenosine, an immunosuppressive metabolite. Adenosine, produced from adenosine triphosphate by enzymes CD39 and CD73, binds the adenosine 2a and 2b receptors (A2aR and A2bR) expressed on immune cells and inhibits critical components of the antitumor immune response. Human PDAC expresses high levels of CD73, which is strongly associated with worse progression-free survival. Preclinical investigation has demonstrated CD73 and A2aR inhibition enhances antitumor immune responses, including increasing activity of ICB. The goal of this study is to test inhibition of the adenosine immunosuppressive pathway in combination with ICB and SBRT in patients with advanced PDAC who are candidates for surgical resection after receiving neoadjuvant chemotherapy. Methods: This investigator-initiated, open-label, multicenter, phase 2 clinical trial will randomize patients with borderline resectable or locally advanced PDAC who have completed 8 cycles of neoadjuvant mFOLFIRINOX and are eligible for SBRT to one of three treatment arms: zimberelimab (anti-PD-1) alone (Arm A), zimberelimab plus quemliclustat (anti-CD73) (Arm B), or zimberelimab plus quemliclustat and etrumadenant (A2aR/A2bR inhibitor)(Arm C) for a period of 7 weeks prior to undergoing surgical resection. 40 Gy SBRT in 5 fractions, totaling a biologically effective dose (BED) of 72 Gy, will be delivered concurrently to all randomized patients starting week 2 of study treatment. Part I will comprise a six-patient safety run-in with a dose-de-escalation design in which patients will be treated according to Arm C with a plan for subsequent enrollment of 14 additional patients per arm (N=42) in Part II. The primary endpoint is CD8+ T-cell infiltration at the time of surgery compared between combination arms and Arm A. Group sample sizes of 14 achieve at least 80% power to detect an effect size of 1.23 with a significance level (alpha) of 0.05 using a two-sided two-sample t-test and adjustment for 2 comparisons. Secondary objectives include estimation of median OS, 18-month survival rate, R0 resection rate, safety profile and CA 19-9 biomarker response. Exploratory studies interrogating the tumor immune microenvironment will be performed on surgical resection specimens. The trial was opened for enrollment on May 19 th , 2023. Clinical trial information: NCT06048484 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2024.42.3_suppl.TPS714
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2024
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  • 2
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    A phase II study of the combination of pexidartinib and sirolimus to target tumor-associated macrophages in unresectable malignant peripheral nerve sheath tumors.
    American Society of Clinical Oncology (ASCO) ; 2024
    In:  Journal of Clinical Oncology Vol. 42, No. 16_suppl ( 2024-06-01), p. 11565-11565
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 42, No. 16_suppl ( 2024-06-01), p. 11565-11565
    Abstract: 11565 Background: Cytotoxic chemotherapy in patients (pts) with unresectable malignant peripheral nerve sheath tumors (MPNSTs) affords minimal benefit with significant toxicity. Pexidartinib, an inhibitor of colony-stimulating factor-1 receptor (CSF1R), targets infiltrating M2 macrophages which correlate with disease progression; combination with an mTOR inhibitor resulted in sustained tumor control in our xenograft MPNST model. A phase I study of pexidartinib + sirolimus suggested the combination’s safety and tumoral static activity where 2 of 6 MPNST pts experienced a progression-free survival (PFS) of 〉 18 weeks. We conducted a phase II study of this combination in pts with unresectable MPNST. Methods: This multicenter, single-arm, investigator-initiated phase 2 trial enrolled pts with unresectable MPNST with 0-3 prior systemic therapies, excluding inhibitors of tyrosine kinases or mTOR. Pts were treated with pexidartinib 1000mg and sirolimus 2mg daily. Tumor response was assessed every 6 weeks by RECIST v1.1. With a target sample size of 25 the study had 90% power to detect a difference of 12 weeks in median PFS assuming a 6 week median PFS in historical controls. Exploratory analysis on pre- and on-treatment tumor biopsies included characterization of the tumor immune microenvironment (TIME) by multiplex immunofluorescence and transcriptional analysis. Results: Fifteen pts enrolled between 1/1/19 and 1/19/23, 14 initiated therapy and are evaluable, including 4 with Neurofibromatosis Type 1 (NF1) associated MPNST. The study was closed to enrollment on 4/12/23 due to lower-than-expected accruals during the COVID-19 pandemic. Data cutoff was 9/20/23. The median age was 39 years (range 19-72) and 28.6% were female. Ten pts had been on prior systemic therapy (median 1). Twelve pts ceased therapy due to disease progression, one died on treatment from COVID-19 before radiologic evaluation, and one stopped therapy due to rash. The median PFS and median overall survival were 6 weeks (95% CI, 6-19.1) and 21.8 weeks (95% CI, 14.6-NA), respectively. One patient achieved confirmed stable disease. Three pts experienced PFS ≥12 weeks and five pts survived 〉 8 months, four of whom had subsequent therapy. One patient was alive at last follow up after 2.7 years. Therapy was well tolerated with grade 3 treatment-related adverse events occurring in 4 (28.6%) pts, namely leukopenia and rash. Exploratory analyses of paired biopsies performed on 8 pts using multiplex immunofluorescence and bulk RNAseq will be presented. At time of submission, no pts remained on study therapy. Conclusions: Cotreatment with pexidartinib and sirolimus has limited efficacy in pts with unresectable MPNST but may benefit a subset of pts. Exploratory analyses of TIME modulation are ongoing. Clinical trial information: NCT02584647 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2024.42.16_suppl.11565
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2024
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  • 3
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    A phase II trial with safety lead-in to evaluate the addition of sotigalimab, a CD40 agonistic monoclonal antibody, to standard-of-care doxorubicin for the treatment of advanced sarcoma.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 11565-11565
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 11565-11565
    Abstract: 11565 Background: Immune checkpoint inhibitors have limited efficacy in soft tissue sarcoma (STS) due to insufficient T-cell activation and infiltration by immunosuppressive macrophages. Sotigalimab (S), a high-affinity humanized monoclonal antibody for CD40, promotes antigen presentation, stimulates T-cell responses, and reprograms immunosuppressive macrophages. Preclinical studies with CD40 agonists revealed efficacy in immune “cold” tumor types and synergy with chemotherapy. Standard first-line doxorubicin (D) provides objective response rate (ORR) 〈 15% and median progression free survival (mPFS) of 4-6 mos in advanced STS. We therefore conducted this first-in-human study of D+S in STS. Methods: An open-label, single-arm, multi-center, phase 2 study evaluated D+S in advanced STS. Pts had ECOG PS ≤ 1 and any number of prior lines (but were anthracycline-naïve). The study initially enrolled all STS subtypes (except KS and GIST) but was amended in 12/2020 to limit enrollment to dedifferentiated liposarcoma (DDLPS), leiomyosarcoma (LMS), and undifferentiated pleomorphic sarcoma (UPS). Pts received D 75 mg/m 2 IV D1 + S 0.3 mg/kg IV D1 for eight 21-day cycles, followed by S monotherapy. A safety lead-in was performed (first 6 patients). Primary endpoint was ORR. Secondary endpoints included PFS and safety. A Simon two-stage design was used. If ≥ 7/32 responded overall, the treatment would be considered promising (85% power, α = 0.05). A subset of patients underwent paired tumor biopsies. Results: 32 pts have enrolled (median age 62; 10 LMS, 10 UPS, 9 DDLPS, 3 other). 4 pts remain on treatment with median follow-up of 2.8 mos (1 UPS pt has not reached first imaging). D (75 mg/m2) + S (0.3 mg/kg) was safe and tolerable without dose limiting toxicity. Overall ORR was 16% (5/31). Objective responses occurred in UPS (2), LMS (1), other LPS (1), and epithelioid hemangioendothelioma (1). Overall mPFS was 7.5 mos (95% CI 5.6-14.9 mos) and PFS rate at 6 and 12-mos was 55% and 31%, respectively. mPFS by STS subtype was 11.9 mos (95% CI: 10.3 – NE) for DDLPS, 7.5 mos (95% CI: 1.4—NE) for UPS and 5.6 mos (95% CI: 1.3 – NE) for LMS. Overall, 17/31 (55%) pts experienced grade 3 or 4 adverse events (AEs): most commonly, neutropenia (32%), febrile neutropenia (19%), and anemia (16%). 16% of pts experienced cytokine release (all low-grade). Correlative analysis of biopsies with high-definition spatial proteomics is ongoing. Conclusions: D (75 mg/m2) + S (0.3 mg/kg) every 21 days is safe and tolerable in STS. Final analysis of the primary endpoint awaits further follow-up on recently enrolled patients. Subtype-specific analysis suggests improvement in median PFS for DDLPS over historical controls: 11.9 mos vs 4 mos (Stacchiotti S. Ann Oncol 2020; Livingston M. Sci Rep 2017). An expansion of the DDLPS cohort is planned. Clinical trial information: NCT03719430 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.11565
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 4
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    CheMo4METPANC: A phase 2 study with combination chemotherapy (gemcitabine and nab-paclitaxel), chemokine (C-X-C) Motif receptor 4 inhibitor (motixafortide), and immune checkpoint blockade (cemiplimab) in metastatic treatment-naïve pancreas adenocarcinoma.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. TPS4200-TPS4200
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. TPS4200-TPS4200
    Abstract: TPS4200 Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) is a uniformly fatal disease for which treatments result in limited benefit. Failure of immune checkpoint blockade is attributed to multiple immunosuppressive pathways within the tumor microenvironment. The C-X-C motif chemokine receptor 4 (CXCR4)/C-X-C motif chemokine ligand 12 (CXCL12) axis results in exclusion of anti-tumor immune cells. Preclinical studies demonstrated that simultaneous CXCR4 inhibition (CXCR4i) and anti-programmed cell death 1 (aPD1) resulted in tumor stabilization. We extended these findings by testing multiple combinations of CXCR4i, aPD1, and gemcitabine in the KPC mouse model of PDAC. Mice treated with gemcitabine, CXCR4i, and aPD1 (triple therapy) experienced a survival benefit compared to mice treated with either gemcitabine alone, or with CXCR4i/aPD1. Tumors from mice treated with triple therapy demonstrated increased apoptosis and a favorable tumor immune microenvironment (TIME). Motixafortide with pembrolizumab, fluorouracil, and nanoliposomal irinotecan has shown encouraging results in the second-line setting in mPDAC with a confirmed ORR of 13.2% and progression free survival (PFS) of 3.8 months (m). The goal of this first-in-man trial is to test preliminary safety and efficacy of Motixafortide (CXCR4i), Cemiplimab (aPD1), Gemcitabine, and Nab-paclitaxel (MCGN) in treatment naïve mPDAC. Methods: This is an open label, multicenter, investigator-initiated simon-2-stage phase 2 clinical trial in mPDAC testing MCGN. The study includes a six-patient safety run-in cohort and an additional 4 patients comprising a pilot efficacy signal seeking study (N=10). If ≥3 of the 10 patients within the pilot stage were to experience a partial response (PR) by RECIST criteria within 16 weeks, the combination would be considered promising and an expansion cohort of an additional 30 patients was planned. On 09/21/22, we amended the study to forego the planned open-label expansion cohort (N=30) and transition directly to a randomized phase 2 trial testing MCGN compared toGemcitabine and Nab-paclitaxel (GN) alone (N=102), after completion of the pilot phase of the study. The primary endpoint is PFS. The study has 80% power to detect an improvement in PFS from 6 to 9.2 m (HR 0.65) with a one-sided alpha of 0.20. One interim analysis for futility is planned when 50% of the PFS events are observed. Secondary objectives include ORR, disease control rate, duration of clinical benefit and OS. Required (pilot portion) and optional (randomized portion) paired tumor biopsies will undergo exploratory analysis including interrogation of the TIME. This trial was started in September 2020 and has enrolled 10 patients to the pilot stage as of 02/2023. Clinical trial information: NCT04543071 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.TPS4200
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
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  • 5
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    Chemotherapy and Immune Checkpoint Blockade for Gastric and Gastroesophageal Junction Adenocarcinoma
    American Medical Association (AMA) ; 2023
    In:  JAMA Oncology Vol. 9, No. 12 ( 2023-12-01), p. 1702-
    Details
    In: JAMA Oncology, American Medical Association (AMA), Vol. 9, No. 12 ( 2023-12-01), p. 1702-
    Abstract: Combining immune checkpoint blockade (ICB) with chemotherapy improves outcomes in patients with metastatic gastric and gastroesophageal junction (G/GEJ) adenocarcinoma; however, whether this combination has activity in the perioperative setting remains unknown. Objective To evaluate the safety and preliminary activity of perioperative chemotherapy and ICB followed by maintenance ICB in resectable G/GEJ adenocarcinoma. Design, Setting, and Participants This investigator-initiated, multicenter, open-label, single-stage, phase 2 nonrandomized controlled trial screened 49 patients and enrolled 36 patients with resectable G/GEJ adenocarcinoma from February 10, 2017, to June 17, 2021, with a median (range) follow-up of 35.2 (17.4-73.0) months. Thirty-four patients were deemed evaluable for efficacy analysis, with 28 (82.4%) undergoing curative resection. This study was performed at 4 referral institutions in the US. Interventions Patients received 3 cycles of capecitabine, 625 mg/m 2 , orally twice daily for 21 days; oxaliplatin, 130 mg/m 2 , intravenously and pembrolizumab, 200 mg, intravenously with optional epirubicin, 50 mg/m 2 , every 3 weeks before and after surgery with an additional cycle of pembrolizumab before surgery. Patients received 14 additional doses of maintenance pembrolizumab. Main Outcomes and Measures The primary end point was pathologic complete response (pCR) rate. Secondary end points included overall response rate, disease-free survival (DFS), overall survival (OS), and safety. Results A total of 34 patients (median [range] age, 65.5 [25-90] years; 23 [67.6%] male) were evaluable for efficacy. Of these patients, 28 (82.4%) underwent curative resection, 7 (20.6%; 95% CI, 10.1%-100%) achieved pCR, and 6 (17.6%) achieved a pathologic near-complete response. Of the 28 patients who underwent resection, 4 (14.3%) experienced disease recurrence. The median DFS and OS were not reached. The 2-year DFS was 67.8% (95% CI, 0.53%-0.87%) and the OS was 80.6% (95% CI, 0.68%-0.96%). Treatment-related grade 3 or higher adverse events for evaluable patients occurred in 20 patients (57.1%), and 12 (34.3%) experienced immune-related grade 3 or higher adverse events. Conclusion and Relevance In this trial of unselected patients with resectable G/GEJ adenocarcinoma, capecitabine, oxaliplatin, and pembrolizumab resulted in a pCR rate of 20.6% and was well tolerated. This trial met its primary end point and supports the development of checkpoint inhibition in combination with perioperative chemotherapy in locally advanced G/GEJ adenocarcinoma. Trial Registration ClinicalTrials.gov Identifier: NCT02918162
    Type of Medium: Online Resource
    ISSN: 2374-2437
    URL: Article
    DOI: 10.1001/jamaoncol.2023.4423
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2023
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  • 6
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    A phase IV study of ApricityCARE program for cancer adverse events rapid evaluation to improve treatment outcomes of ethnic/racial minority patients with non-small cell lung cancer (NSCLC) receiving immune checkpoint inhibitors (ICI).
    American Society of Clinical Oncology (ASCO) ; 2024
    In:  Journal of Clinical Oncology Vol. 42, No. 16_suppl ( 2024-06-01), p. TPS1642-TPS1642
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 42, No. 16_suppl ( 2024-06-01), p. TPS1642-TPS1642
    Abstract: TPS1642 Background: ICI have changed the treatment landscape of NSCLC, with many now FDA approved in not just advanced, but even early-stage disease. With the increase in ICI use, the incidence of immune-related adverse effects (irAEs) has also risen, occurring in up to 16% of ICI-treated patients. Prompt recognition and timely management are necessary to avert potential poor outcomes from direct toxicity and/or early treatment discontinuation. However, existing barriers to access care that disproportionately impact racial and ethnic minority patients may amplify challenges in early, effective management of irAEs. Using technology-enabled health interventions in a culturally competent manner can improve access to health care resources and reduce health disparities. These platforms need to be optimized at the technology and health literacy level of underserved minority communities and adapted to meet the community's needs. Methods: We have designed a multi-center phase IV clinical trial to 1) assess factors related to suboptimal and optimal use of the ApricityCARE, a virtual first-response clinical support (or coverage) to provide 24/7 symptom monitoring and side effect management and 2) determine the impact of the program on ICI toxicity management for NSCLC patients receiving ICIs in a highly diverse community. Eligible patients are those with a confirmed diagnosis of NSCLC who self-identify as a member of an ethnic minority or underserved population, prescribed for any treatment regimen that includes an ICI. The study entails a 50-patient run-in phase with two focus group discussions, stratified on a Likert-type scale based on the frequency of utilization, to determine factors impacting usability of the ApricityCare program. This data will inform optimal implementation of ApricityCare for the randomized phase of the study, where 230 patients will be assigned 1:1 to use of ApricityCare versus standard of care. The run-in phase of the study is currently accruing at Columbia University, and is planned to open at NYU, Mount Sinai, and Montefiore (NCT05812274). Clinical trial information: NCT05812274 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2024.42.16_suppl.TPS1642
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2024
    detail.hit.zdb_id: 2005181-5
    detail.hit.zdb_id: 604914-X
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  • 7
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    A phase II, open label, single arm study of nivolumab for recurrent or progressive IDH mutant gliomas with prior exposure to alkylating agents.
    American Society of Clinical Oncology (ASCO) ; 2024
    In:  Journal of Clinical Oncology Vol. 42, No. 16_suppl ( 2024-06-01), p. 2056-2056
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 42, No. 16_suppl ( 2024-06-01), p. 2056-2056
    Abstract: 2056 Background: Somatic mutations in isocitrate dehydrogenase 1 (IDH) are recognized as an important prognostic factor in patients with gliomas and are associated with longer survival. Regardless of initial grade, however, recurrence and transformation into higher grade tumors is almost universal. IDH-mutant gliomas are prone to develop hypermutation after exposure to alkylating agents; in other solid tumors, hypermutation may be a predictive biomarker for PD-1 inhibitor response. In this multicenter phase 2, open label, single arm study, we hypothesize that this specific subgroup of patients would demonstrate a clinically meaningful benefit from nivolumab as measured by overall response rate (ORR), duration of response (DOR), median progression-free survival (PFS), and overall survival (OS). Methods: Eligible patients aged 18 years and older with recurrent or progressive IDH-mutant (WHO Grades 2, 3, or 4) gliomas were included. All had prior exposure to alkylating agents. Nivolumab was given 240 mg q2w for 8 cycles, then 480 mg q4w until disease progression, unacceptable toxicity, withdrawal of consent, or completion of study at 2 years. Efficacy was evaluated by ORR of partial (PR) and complete responses (CR) based on RANO criteria; for patients with non-enhancing disease only, low-grade glioma RANO criteria was used. Secondary endpoints included median PFS and median OS, as well as DOR. Toxicity assessments continued for two safety monitoring follow-up visits off study. Survival follow-up occurred every 3 months until death or until study completion at 2 years. Results: Thirty-five patients were enrolled, with 33 (66.7% male) evaluable at study completion. Histology consisted of oligodendroglioma (N=11; 55% Grade 3) and astrocytoma (N=22; 36% Grade 3, 32% Grade 4). Median number of prior line of systemic therapy was 1 (range 1-6). Median dexamethasone dose at screening was 0 mg (range 0-4) and at end of study was 0 mg (range 0-8). ORR was 9% with two PR and one CR, with median DOR of 33 months. All three patients maintained response at 20+ (Grade 3 oligodendroglioma), 33+ (Grade 3 astrocytoma) and 51+ months (Grade 2 astrocytoma). 11 (33%) patients had stable disease (8 were stable for over 6 months) with median PFS of 2.2 months and median OS of 31 months. Nivolumab was well-tolerated with two treatment-related Grade 3 adverse events (lymphopenia and hypotension). One patient discontinued treatment due to Grade 2 transaminitis. Conclusions: Nivolumab was well-tolerated with no unexpected toxicity in this brain tumor population. Three patients derived a prolonged response and still continue on CR and PR after completing 24 months of planned treatment. This study provides data on single-agent PD-1 inhibition, which will serve as baseline efficacy data for ongoing and future combination immunotherapy trials with PD-1 inhibitors in recurrent IDH-mutant gliomas. Clinical trial information: NCT03557359 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2024.42.16_suppl.2056
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2024
    detail.hit.zdb_id: 2005181-5
    detail.hit.zdb_id: 604914-X
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  • 8
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    A Single-Arm Phase II Trial of Sitravatinib in Advanced Well-Differentiated/Dedifferentiated Liposarcoma
    American Association for Cancer Research (AACR) ; 2023
    In:  Clinical Cancer Research Vol. 29, No. 6 ( 2023-03-14), p. 1031-1039
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 29, No. 6 ( 2023-03-14), p. 1031-1039
    Abstract: To evaluate sitravatinib, an inhibitor of multiple receptor tyrosine kinases (RTK), for the treatment of well-differentiated/dedifferentiated liposarcoma (WD/DD LPS). Patients and Methods: This multicenter, open-label, Phase II trial enrolled patients with advanced WD/DD LPS who had received at least one prior systemic regimen and had progression within 12 weeks of enrollment. Patients received sitravatinib 150 mg (later amended to 120 mg) orally daily. A Simon two-stage design was used to evaluate for an improvement in the primary endpoint, progression-free rate at 12 weeks (PFR12), from 20% to 40%. Secondary endpoints included antitumor activity and safety. A subset of patients underwent paired biopsies analyzed using reverse-phase protein array. Results: Twenty-nine patients enrolled. Median age was 62 years and 31% had received 3 or more prior lines. Most patients (93%) had DDLPS or mixed WD/DD LPS. Overall, 12 of 29 patients (41%) were alive and progression-free at 12 weeks and the study met the primary endpoint. There were no confirmed responses. Median progression-free survival was 11.7 weeks [95% confidence interval (CI): 5.9–35.9] and median overall survival was 31.7 weeks (95% CI: 18.1–90.1). The most common treatment-related adverse events were diarrhea (59%), hypertension (52%), hoarseness (41%), mucositis (31%), and nausea (31%). Baseline expression of phosph o-RTKs was not significantly different between patients with and without clinical benefit from sitravatinib, but the number of samples was small. Conclusions: Sitravatinib provided a PFR12 of 41% and meaningful disease control in a subset of patients with advanced, progressive WD/DD LPS.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-22-3351
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 1225457-5
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  • 9
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    CheMo4METPANC: A randomized phase 2 study with combination chemotherapy (gemcitabine and nab-paclitaxel), chemokine (C-X-C) motif receptor 4 inhibitor (motixafortide), and immune checkpoint blockade (cemiplimab) compared to chemotherapy alone in metastatic treatment-naïve pancreatic adenocarcinoma.
    American Society of Clinical Oncology (ASCO) ; 2024
    In:  Journal of Clinical Oncology Vol. 42, No. 16_suppl ( 2024-06-01), p. TPS4208-TPS4208
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 42, No. 16_suppl ( 2024-06-01), p. TPS4208-TPS4208
    Abstract: TPS4208 Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) carries a 5-year relative survival of 3%. Immune checkpoint inhibitors have thus far failed to improve outcomes due to an immunosuppressive tumor microenvironment (TME). Signaling through the C-X-C motif chemokine receptor 4 (CXCR4)/C-X-C motif chemokine ligand 12 (CXCL12) axis results in exclusion of anti-tumor immune cells in mouse PDAC models. Longitudinal survival studies testing combinations of CXCR4i, aPD-1, and gemcitabine in the KPC mouse model of PDAC demonstrated a survival benefit with the combination of all three agents. Results from a multicenter, investigator-initiated, single arm pilot study evaluating the preliminary safety and efficacy ofMotixafortide (CXCR4i), Cemiplimab (aPD1), Gemcitabine, and Nab-paclitaxel (MCGN) in 11 patients with treatment-naïve mPDAC were recently presented. Seven patients (64%) achieved a partial response, including 6 confirmed partial responses, and 10 patients (91%) had disease control, compared to historic partial response and disease control rates of 23% and 48%, respectively, with gemcitabine and nab-paclitaxel (GN). Preliminary median progression-free survival (PFS) was 9.6 months compared to historic median PFS of 5.5 months with GN. Analysis of paired pre- and on-treatment biopsy samples from demonstrated an increase in CD8+ T-cell density in tumors from all 11 patients treated with MCGN (p=0.007). Based on these promising results, the protocol was amended from a single arm expansion totaling 40 patients to a randomized phase 2 study. Methods: This is an open-label, multicenter, investigator-initiated phase 2 clinical trial. Patients are randomized 2:1 to receive MCGN or GNalone (N=108). The primary endpoint is progression free survival. The study has 80% power to detect an improvement in PFS from 6 to 9.2 months (HR 0.65) with a one-sided alpha of 0.20. One interim analysis for futility is planned when 50% of the PFS events are observed. Secondary objectives include response rate, disease control rate, duration of clinical benefit and overall survival. Patients will undergo optional paired biopsies which will be analyzed in conjunction with samples collected from the phase I pilot study. Exploratory studies include interrogation of the TME using quantitative multiplex immunofluorescence and single-cell RNA sequencing. The randomized phase 2 trial is open to enrollment and one patient has been randomized as of 1/29/2024. Clinical trial information: NCT04543071 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2024.42.16_suppl.TPS4208
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2024
    detail.hit.zdb_id: 2005181-5
    detail.hit.zdb_id: 604914-X
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  • 10
    Online Resource
    Online Resource
    A randomized phase Ib/II study of intermittent androgen deprivation therapy plus nivolumab with or without interleukin-8 blockade in men with hormone-sensitive prostate cancer (MAGIC-8).
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. 5082-5082
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 5082-5082
    Abstract: 5082 Background: Immunotherapy has limited efficacy in castration-resistant prostate cancer. Androgen deprivation therapy (ADT) has significant immunomodulatory effects and initially induces a complex immune infiltrate before castration-resistance develops. However, ADT also recruits immunosuppressive myeloid cells to the tumor microenvironment by increasing interleukin-8 (IL-8). We conducted a phase Ib/II clinical trial of immunotherapy plus ADT in men with recurrent castration-sensitive prostate cancer (CSPC). We hypothesized that anti-PD-1 (nivolumab) +/- anti-IL-8 (BMS-986253) given at the time of castration could induce anti-tumor immune responses and decrease disease progression. Methods: MAGIC-8 was a multicenter, phase Ib/II study evaluating nivolumab +/- BMS-986253 combined with a short course of degarelix acetate in patients with recurrent CSPC and rapid PSA doubling time (≤ 12 mos). In the Phase Ib portion, patients were treated with nivolumab (480mg Q4W) for 8 wks followed by nivolumab plus degarelix for an additional 16 wks. In the phase II portion, patients were randomized 1:2 to nivolumab + degarelix (Arm A) versus nivolumab + BMS-986253 (2400mg Q2W) + degarelix (Arm B). The primary endpoints were PSA recurrence at 10 mos following randomization and safety. Key secondary endpoints included biochemical recurrence-free survival (bPFS), time to recovery of testosterone ( 〉 150ng/dl), and bPFS after recovery of testosterone. Results: Between October 16, 2019 and March 9, 2021, 59 patients were enrolled. The first 15 patients were treated on Arm A followed by 1:2 randomization to Arm A (N = 15) versus Arm B (N = 29). Median follow up was 11.6 mos at the data cutoff (1/24/22). Patients treated on Arm A had a significantly lower rate of PSA relapse (17.39%) at 10 mos compared to historical controls (p = 〈 0.001), including a subgroup of patients (6.67%) with recovery of testosterone and no PSA relapse at 〉 2 years of follow up. Median time-to-recovery of testosterone was 12.7 mos, median bPFS was 14.0 mos and median bPFS after recovery of testosterone was 5.5 mos. In Arm B, there was no difference in PSA relapse at 10 mos (35%, p = 0.09), median time-to-recovery of testosterone, median bPFS and median bPFS after recovery of testosterone compared to historical controls. Treatment in both arms was well tolerated with a lower rate of grade 3-4 treatment-related adverse events in Arm B compared to Arm A (3.5% vs 12.9%). Conclusions: A short course of ADT plus nivolumab may decrease the rate of PSA relapse and lead to durable long-term responses after recovery of testosterone in a subset of patients. These data support further evaluation of combining nivolumab with ADT in CSPC. Although the addition of BMS-986253 did not improve rate of PSA relapse, we observed significantly less toxicity with the addition of IL-8 inhibition. Clinical trial information: NCT03689699.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.5082
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
    detail.hit.zdb_id: 604914-X
    Location Call Number Limitation Availability
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