Intrathecal (IT) and intravenous (IV) nivolumab (N) for metastatic melanoma (MM) patients (pts) with leptomeningeal disease (LMD).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9519-9519
Author(s):  
Ida John ◽  
Alexandra P. Foster ◽  
Cara L. Haymaker ◽  
Roland L. Bassett ◽  
J. Jack Lee ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Metastatic Melanoma ◽  
Human Study ◽  
Maximum Tolerated Dose ◽  
Leptomeningeal Disease ◽  
Combination Regimen ◽  
Multiple Time ◽  
Csf Cytology ◽  
Open Label ◽  
Dismal Prognosis

9519 Background: MM pts with LMD have a dismal prognosis, with median overall survival (OS) < 3 months, no approved therapies and extremely limited clinical trial options. We previously reported initial safety findings from an open label, single arm, single center phase I/IB trial (NCT03025256), in which IT and IV N were well tolerated, without any CNS-specific or unexpected toxicity. Here we report an update on safety and maximum tolerated dose (MTD) for all patients enrolled, and efficacy for the completed dose cohorts. Methods: MM patients aged >18 with evidence of LMD by MRI and/or CSF cytology, ECOG PS ≤2 were treated with IT and IV N. Dexamethasone ≤4mg/daily and concurrent BRAF/MEK inhibitor(i) treatment was allowed. For cycle 1, IT N was administered via intraventricular reservoir on day (D)1. For subsequent cycles (every 14 days), pts received IT N on D1, followed by IV N 240 mg on D2. IT N doses evaluated were 5, 10, 20 mg and 50 mg. Blood and CSF were collected at multiple time points for translational research. The primary objectives of this first-in-human study were to determine the safety and MTD of IT N given with IV N in MM pts with LMD. Bayesian mTPI methodology was used to define the MTD. Results: To date, 23 pts have been treated: two at 5, three at 10, fourteen at 20 mg and four at 50 mg IT N. Median age at LMD diagnosis was 42 (28-73); 12 pts are male. All pts had radiographic evidence of LMD and neurological symptoms; 14 pts had positive CSF cytology at baseline. 21 pts received prior therapies for their metastatic melanoma: anti-PD1 (n = 19), BRAFi/MEKi (n = 14), chemo (n = 2), IT IL2 (n = 4) other (n = 2). 19 pts had prior XRT, including whole brain RT (n = 7). Two pts were treatment-naïve. The median number of IT N doses was five (1- 66). The combination regimen was well tolerated by all evaluable pts (n=23), with only five pts (22%) experiencing gr 3 AEs, and no reported gr 4 or 5 toxicities. Nausea (30%), diarrhea (26%), and rash (22%) were the most common AEs. Eight pts (23%) experienced AEs after IT N administration, all gr 1. Initial efficacy analysis included only pts (n=19) treated with first three dose levels (5-20mg). Median follow-up for these pts is 4.5 months (mos) (1.1, 31.5 mos) and median OS is 63 % at 3 mos, 42 % at 6 mos and 30% at 12 mos. Conclusions: The trial demonstrates the feasibility and safety of IT administration of modern immunotherapy for MM pts with LMD. No unexpected systemic or neurological toxicity was observed with 20mg IT N. 2 additional patients are required to complete the 50mg IT N cohort. OS rates at 6 and 12 mos are encouraging and support further evaluation of IT administration of immunotherapy agents for pts with MM and LMD. Final presentation will include results of LMD for all dose cohorts, composite response assessment and comparative analysis of longitudinal CSF samples to assess immunologic effects. Clinical trial information: NCT03025256.

Single-center phase I/Ib study of concurrent intrathecal (IT) and intravenous (IV) nivolumab (N) for metastatic melanoma (MM) patients (pts) with leptomeningeal disease (LMD).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 10008-10008 ◽  
Author(s):  
Isabella Claudia Glitza ◽  
Suzanne Phillips ◽  
Courtney Brown ◽  
Cara L. Haymaker ◽  
Roland L. Bassett ◽  
...  
Keyword(s):  
Translational Research ◽  
Interleukin 2 ◽  
Human Study ◽  
Response Assessment ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Leptomeningeal Disease ◽  
Multiple Time ◽  
Csf Cytology ◽  
Dismal Prognosis

10008 Background: MM pts with LMD have a dismal prognosis, with a median overall survival (OS) < 3 months and no approved therapies. IT administration of interleukin-2 (IL2) achieves survival in ~15% of MM LMD pts, but at cost of severe toxicities. Given the favorable clinical activity and safety of systemic anti-PD1, we hypothesized that IT N administration is safe and can achieve clinical benefit in pts with LMD. Methods: The primary objectives of this first-in-human study (NCT03025256) were to determine the safety and the maximum tolerated dose (MTD) of IT N given with IV N in MM pts with LMD. Eligible pts had MM, ECOG PS < / = 2, and evidence of LMD by MRI and/or CSF cytology. Dexamethasone < / = 4mg/daily was allowed. For cycle 1, IT N is administered via intraventricular reservoir on day (D) 1; Blood and CSF is collected at multiple time points for translational research. For subsequent cycles (every 14 days), pts receive IT N on D1, followed by IV N 240 mg on D2. IT N doses evaluated were 5, 10, and 20 mg. Bayesian mTPI methodology was used to define the MTD. The study was recently amended to allow for concurrent BRAF/MEK inhibitor(i) treatment. Results: To date, 15 pts have been treated: two at 5, three at 10, and 10 at 20 mg IT N. Median age at LMD diagnosis was 41.8 (30.9-73.2) years; 6 pts are male. All pts had radiographic evidence of LMD and neurological symptoms; 8 pts had positive CSF cytology. 12 pts received prior therapies for their MM: anti-PD1 (n = 11), BRAFi/MEKi (n = 9), chemo (n = 2), IT IL2 (n = 4) other (n = 2). 11 pts had prior XRT, including whole brain RT (n = 7). 1 pt was treatment-naïve. The median numbers of IT N doses was 4 (1-42). No grade (Gr) 4-5 AEs were attributed to IT N or IV N; only 4 events (Gr 1, n = 2; Gr2, n = 2) were possibly related to the IT N. With a median follow-up of 18.7 weeks (1-83.3 wks), the median OS is 46.1 weeks (0.1-83.3). Clinical response data, translational research endpoints, including changes in CSF cytokines and cfDNA, will be reported. Conclusions: The trial demonstrates the feasibility of prospective clinical trials in MM patients with LMD. The combination of IT/ IV N was safe and well-tolerated, with no unexpected systemic or neurological toxicity. Final presentation will include results of LMD composite response assessment, comparative analysis of longitudinal CSF/blood samples to assess immunologic effects. Finally, the interim OS of the patients is encouraging, and supports further evaluation of IT administration of immunotherapy agents for pts with MM and LMD. Clinical trial information: NCT03025256.

scholarly journals DIPG-52. PHASE I CLINICAL TRIAL OF ONC201 IN PEDIATRIC H3 K27M-MUTANT GLIOMA OR NEWLY DIAGNOSED DIPG

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii297-iii297
Author(s):  
Sharon Gardner ◽  
Rohinton Tarapore ◽  
Jeffrey Allen ◽  
Wafik Zaky ◽  
Yazmin Odia ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Body Weight ◽  
Phase I ◽  
Single Agent ◽  
High Grade Glioma ◽  
Newly Diagnosed ◽  
Liquid Formulation ◽  
Open Label ◽  
Dismal Prognosis ◽  
Expansion Cohort

Abstract H3 K27M-mutant gliomas often manifest as midline gliomas, have a dismal prognosis, and have no effective treatments. ONC201 efficacy has been shown in high-grade glioma preclinical models and durable responses with single agent ONC201 have been reported in adults with recurrent H3 K27M-mutant gliomas. These observations led to a Phase I pediatric clinical trial of ONC201 dosed by body weight. This multi-center, open-label, 3 + 3 dose-escalation and dose-expansion clinical trial (NCT03416530) for H3 K27M-mutant glioma or non-biopsied DIPG has 6 arms: arms A and E determine the RP2D in pediatric post-radiation (recurrent or not-recurrent) H3 K27M-mutant glioma patients with ONC201 administered as an oral capsule as well as a liquid formulation, respectively. Both arms have completed accrual. The study is currently enrolling newly diagnosed DIPG patients to determine the RP2D for ONC201 in combination with radiation (arm B). Dedicated assessment of intratumoral ONC201 concentrations in midline gliomas patients (arm C) and the effects of ONC201 in H3K27M DNA levels in circulating CSF (arm D) are currently enrolling patients. ONC201 as a single agent in patients with progressive H3K27M mutant tumors following irradiation (excluding DIPG/spinal cord tumors) was recently opened (arm F). Once the RP2D is confirmed, there is a dose-expansion cohort to confirm the safety, radiographic efficacy and survival with ONC201. The primary endpoints of arms A, B, and E have been established with the RP2D of 625mg scaled by body weight as a capsule or liquid formulation administered alone or in combination with radiation without incidence of dose-limiting toxicity.

Early safety and efficacy from a phase I open-label clinical trial of CD137(4-1BB) agonistic antibody LVGN6051 as monotherapy and in combination with pembrolizumab.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2521-2521
Author(s):  
Siqing Fu ◽  
Wael A. Harb ◽  
Sapna Pradyuman Patel ◽  
Charles Lu ◽  
Daniel M. Halperin ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Antitumor Activity ◽  
Safety Profile ◽  
Single Agent ◽  
Human Study ◽  
Hepatic Metastases ◽  
Preliminary Evidence ◽  
Open Label ◽  
Grade 3 ◽  
Favorable Safety

2521 Background: LVGN6051, a monoclonal antibody against CD137 (also known as 4-1BB or TNFRSF9) with an engineered Fc capable of selectively binding to the Fcγ receptor IIB, acts as a conditional CD137 agonist, resulting in immune activation optimally in tumor microenvironment ( Qi, Nat. Commun. 2019 ). In preclinical models, LVGN6051 demonstrated robust anti-tumor efficacy and safety as a single agent and in combination with anti-PD-1 antibodies. Therefore, we have initiated this first-in-human study of LVGN6051 alone or in combination with pembrolizumab for the treatment of advanced or metastatic malignancy. Methods: This study includes accelerated dose escalation monotherapy up to 2 mg/kg of LVGN6051, and traditional 3 + 3 design for higher doses of LVGN6051 alone or in combination with pembrolizumab. Then, this study will enroll patients with specific types of malignancies following Simon’s two-stage design. Both agents are administered once every 3 weeks. Primary objectives of this study were to define the safety profile and to establish the recommended phase 2 dose (RP2D) of LVGN6051 alone or in combination with pembrolizumab. Pharmacokinetics, immunogenicity, pharmacodynamics and clinical efficacy will be also evaluated. Results: At the cut-off date on January 18, 2021, 16 subjects have been enrolled into the monotherapy cohorts (n=12, no DLT observed up to 7 mg/kg), and the combination cohort (n=4, ongoing at LVGN6051 2 mg/kg and pembrolizumab 200 mg, one DLT observed). No treatment-related adverse event (TRAE) was observed in monotherapy. Treatment-emergent adverse events (TEAE) in combination included increased ALT/AST, thrombocytopenia, and fatigue. In the combination cohort, one patient with predominant hepatic metastases and history of intermittent grade 2 hepatic impairment experienced grade 3 increased ALT/AST (DLT) on cycle 1 day 15 that were resolved to her baseline without corticosteroids on cycle 1 day 18. TRAE included increased ALT/AST, thrombocytopenia, neutropenia, nausea and fatigue. Seven of 10 evaluable patients in the monotherapy cohorts demonstrated stable disease with the longest treatment being 8+ months. Tumor reductions by >10% were observed in melanoma and neuroendocrine tumor on monotherapy. One patient with metastatic head and neck squamous cell carcinoma who had progressed on an anti-PD-L1 based therapy showed an immune partial response (iPR) for 6+ months to the combination therapy. Conclusions: Preliminary evidence showed that LVGN6051 was well tolerated and tumor shrinkages were observed. While we continue assessing its safety profile, antitumor activity was observed in the LVGN6051 and pembrolizumab cohort. The favorable safety profile and preliminary antitumor activity warrant further evaluation in patients with advanced malignancies. Clinical trial information: NCT04130542.

A phase I/II study combining tosedostat with capecitabine in patients with metastatic pancreatic adenocarcinoma.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. TPS471-TPS471
Author(s):  
Andrea S. Teague ◽  
Manik A. Amin ◽  
Kian-Huat Lim ◽  
Albert C. Lockhart ◽  
Ashiq Masood ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Amino Acids ◽  
Phase I ◽  
Phase Ii ◽  
Primary Objective ◽  
Cellular Stress Response ◽  
Ductal Adenocarcinoma ◽  
Open Label ◽  
Pancreatic Cancer Cells ◽  
Dismal Prognosis

TPS471 Background: Metastatic pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. Recent advances with fluorouracil in combination with oxaliplatin and irinotecan (FOLFIRINOX) and nab-paclitaxel combined with gemcitabine (AG) have improved survival in patients with PDAC. A fluorouracil-based regimen is recommended for patients who progress after a gemcitabine-based regimen. Tosedostat is an oral aminopeptidase inhibitor shown to have anti-proliferative effects in malignancies. Aminopeptidase inhibitors disrupt the cleavage of amino acids from peptides downstream of proteasomal degradation, preventing the recycling of amino acids needed for new protein synthesis. This leads to intracellular depletion of amino acids, resulting in a cellular stress response known as the amino acid deprivation response, which leads to apoptosis. Because pancreatic cancer cells frequently upregulate expression of these aminopeptidases, aminopeptidases inhibitors hold therapeutic promise. Methods: This is a single institution phase I/II open-label trial to evaluate the safety and tolerability of tosedostat plus capecitabine in patients with metastatic PDAC that have progressed after a gemcitabine-based regimen. The phase I part will be conducted in a dose de-escalation fashion, with two planned dose levels of tosedostat (120mg or 60mg) p.o. daily on days 1 to 21 with capecitabine 1000 mg/m2 p.o. BID on days 1 to 14 of a 21-day cycle. If more than one patient in the tosedostat (120 mg) cohort experiences a dose limiting toxicity (DLT), then 6 more patient will be enrolled to the tosedostat (60 mg) cohort. A total of 36 patients will be enrolled in the phase II portion. Primary objective of the phase I portion is to determine the maximum tolerated dose and DLTs of tosedostat and capecitabine combination therapy. Primary objective of the phase II portion is to determine the progression-free survival at 3 months. Secondary objectives are to determine the overall response rate, time-to-progression, overall survival and CA 19-9 response. Exploratory objectives are to explore the predictive molecular biomarkers for treatment response and to explore the prognostic biomarkers. Clinical trial: NCT02352831. Clinical trial information: NCT02352831.

A phase II therapeutic, open label, multi-center clinical trial of NPC-1C, a chimeric monoclonal antibody(mAb), in adults with chemotherapy refractory metastatic colorectal cancer (mCRC), initial results.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 500-500
Author(s):  
Richard D. Kim ◽  
Nilofer Saba Azad ◽  
Michael Morse ◽  
Benjamin R. Tan ◽  
Elizabeth Poplin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trial ◽  
Phase Ii ◽  
Survival Data ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Open Label ◽  
Significance Level ◽  
Initial Results

500 Background: NEO-102 is a novel chimeric mAb targeting a variant of MUC5AC with specificity to colorectal cancer. Its mechanism of action is through antibody dependent cellular cytotoxicity (ADCC). An earlier, phase I study, established the maximum tolerated dose at 3.0 mg/kg IV every 2 weeks with encouraging early signs of clinical activity. We report initial results of the subsequent phase II study. Methods: This is a single arm, open label multi-center clinical trial of NEO-102 in adults with mCRC pts who failed at least two lines of standard chemotherapy (C). An immunohistochemistry (IHC) based companion diagnostic assay was used to select eligible pts whose tumors express the target in > 20% of tumor cells. NEO-102 at 3.0 mg/kg IV was administered q 2 weeks until disease progression. The primary endpoint was OS. A minimum of 43 pts were needed assuming that treatment with NEO-102 will improve OS by 40% (7.0 months) using a one-sided significance level of 10% and 80% power for this study compared to historical control of 5 months. Additional objectives were to evaluate response rate as measured by RECIST criteria and analyze patient PBMCs for ADCC and immune cytokine profiling. Results: A total of 47 pts enrolled were evaluable. 26 pts were male and 35 pts were white. Twenty-four out of 47 pts (51%) remain alive as of September 2015 with an ongoing median OS of 7.0 months (Range 2-22 months). Of these heavily pre-treated pts, 42 were evaluable for response, 13 (31%) demonstrated stable disease by RECIST. Seven pts had more than 4 doses of treatment, maximum 13 doses. Grade 3 adverse events were anemia 1/47 (2%), hyperbilirubinemia 1/47 (2%), diarrhea 1/47 (2%), fatigue 1/47 (2%), headache 1/47 (2%), nausea 1/47 (2%) and vomiting 1/47 (2%). No grade 4 toxicities were reported. Conclusions: In the monotherapy phase 2 study of NEO 102 in patients with refractory mCRC preliminary results demonstrate excellent tolerability and encouraging OS. Updated OS and Progression Free Survival data will be presented at the ASCO 2016 GI Cancers symposium. Additional combination trials with NEO-102 and C are underway. Clinical trial information: NCT01040000.

Phase 1 study to evaluate safety and efficacy of ipilimumab + nivolumab + external beam radiotherapy in patients with metastatic melanoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS9591-TPS9591
Author(s):  
Michael Andrew Postow ◽  
Susan Jane Knox ◽  
Danielle McCabe ◽  
Mary J. Macri ◽  
Paul Schwarzenberger ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Metastatic Melanoma ◽  
Phase 1 ◽  
External Beam Radiotherapy ◽  
Objective Response ◽  
Palliative Therapy ◽  
Dose Fractionation ◽  
High Dose ◽  
Melanoma Metastasis ◽  
Open Label

TPS9591 Background: Immunotherapy (IMT) with checkpoint blocking antibodies has led to progress in metastatic melanoma with 3 FDA-approved drugs, including the combination of ipilimumab (IPI), a CTLA-4 antibody, and nivolumab (NIVO), a PD-1 antibody. Although radiotherapy (RT) is primarily used as local palliative therapy in metastatic melanoma, it also possibly affects systemic antitumor immunity. Preclinical data suggest RT alters the tumor microenvironment and renders tumor cells more susceptible to immunologically-mediated disease regression. These preclinical immunologic effects of RT have been shown to vary by RT dose and fractionation. We are now conducting the first clinical trial in patients to evaluate the triple combination of IPI + NIVO + RT using 2 different dose/fractionation schemes of RT. Methods: This ongoing Phase 1, open-label, multicenter study (NCT02659540) evaluates safety, efficacy, and immunologic effects of IPI + NIVO + RT in 18 patients with unresectable stage IV melanoma. Patients must have 1 melanoma metastasis that can be safely irradiated for palliative purposes and at least 1 measurable lesion that will not be irradiated. Patients receive concurrent IPI (3 mg/kg) and NIVO (1 mg/kg) every 3 weeks (Q3W) x 4, followed by NIVO monotherapy (240 mg Q2W), with RT initiated between the first and second doses of IPI + NIVO. In Cohort A, the irradiated metastasis receives a conventionally fractionated low dose of 30 Gy in 10 fractions of 3 Gy each over 2 weeks. If ≤7 of 9 patients (78%) in Cohort A have Grade 3/4 drug- or radiation-related adverse events, safety is deemed acceptable and Cohort B enrollment opens. In Cohort B, the irradiated metastasis receives a hypofractionated high dose of 27 Gy in 3 fractions of 9 Gy each over 2 weeks. The primary endpoint is safety. Secondary endpoints are objective response rate and disease control rate by RECIST and immune-related RECIST measured at Weeks 12 and 18, duration of response, progression-free survival, and overall survival. Exploratory endpoints include correlative studies of immunological effects. Enrollment opened on 05 Aug 2016. As of 31 Dec 2016, 4 patients are enrolled in Cohort A; enrollment is ongoing. Clinical trial information: NCT02659540.

Phase I-II open label multicenter study of PD0332991 in BRAFV600mut metastatic melanoma patients harboring CDKN2A loss and RB1 expression and treated with vemurafenib.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9545-9545
Author(s):  
Baptiste Louveau ◽  
Matthieu Resche-Rigon ◽  
Thierry Lesimple ◽  
Marc Pracht ◽  
Barouyr Baroudjian ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Phase I ◽  
Clinical Response ◽  
Metastatic Melanoma ◽  
Maximum Tolerated Dose ◽  
Fixed Dose ◽  
Open Label ◽  
Melanoma Patients ◽  
Group 2 ◽  
Group 1

9545 Background: Among mechanisms of resistance to BRAF inhibitors (BRAFi), cell cycle effectors including CDK4 have been involved in ERK reactivation. In this phase I-II open label study, we aimed to establish the Maximum Tolerated Dose (MTD) of PD0332991, an inhibitor of CDK4/6, when added to vemurafenib (VM) in metastatic melanoma patients. Methods: Patients with BRAFV600E/K mutated metastatic melanoma harbouring CDKN2A loss and RB1 expression were included. Patients were treated with a 14 days followed by 7 days rest daily dosing schedule of PD0332991 + continuous BID dosing of VM, and stratified into 2 groups according to previous BRAFi treatment (no group 1, yes group 2). Dose levels (PD0332991 (mg/QD)/VM (mg/BID) ranged from 25/720 to 200/960. The primary endpoint was the occurrence of a DLT within the first 2 cycles of therapy. Secondary endpoints included best response (RECIST), OS, PFS, pharmacokinetics parameters, tumour molecular profiling on baseline lesions using transcriptomic and NGS analysis. Results: Nineteen patients were enrolled, among them 16 (84%) in group 2, with 18.5 months median follow-up. Characteristics at baseline were: male 11 (58%), median age 54.4 years, unresectable stage IIIC 2 (11%), stage IV 17 (89%), M1C 12 (67%), high LDH 9 (47%), median time from advanced melanoma diagnosis to inclusion 26.8 months, ≥ 2 lines therapy 13 (68%). A DLT was observed for 1 and 5 patients in group 1 and 2 respectively, defining the MTD at PD0332991 25mg and VM 960mg in group 2. No significant evidence for drug-drug interaction between PD0332991 and VM was highlighted. In group 2, ORR was estimated to 4 (25%), SD to 8 (50%), median PFS to 9.3 months and median OS to 13.2 months. Baseline transcriptomic analysis revealed high alteration rate associated with clinical response and enrichment in genes related to MAPK, cell cycle and apoptosis pathways. Conclusions: While combination of fixed dose of PD0332991 + VM did not allow us to increase PD0332991 dosage above 25mg, significant clinical benefit was achieved in heavily pretreated patients; baseline molecular analysis revealed an association between transcriptomic data and clinical response. Clinical trial information: NCT02202200.

Replacement of ixazomib for relapsed/refractory multiple myeloma patients refractory to a bortezomib or carfilzomib-containing combination therapy.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 8013-8013 ◽  
Author(s):  
James R. Berenson ◽  
Alexa Cohen ◽  
Tanya M. Spektor ◽  
Jacob D. Bitran ◽  
Gigi Qiqi Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Proteasome Inhibitor ◽  
Phase 1 ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
The Other ◽  
Clinical Activity ◽  
Combination Regimen ◽  
Open Label ◽  
Combination Regimens

8013 Background: The proteasome inhibitor (PI) ixazomib (Ixz) is the first orally administered PI approved for treating multiple myeloma (MM). It has shown clinical activity as a single agent and when used in other combinations. In this phase 1/2 trial, we evaluated Ixz as a replacement therapy for bortezomib or carfilzomib for MM patients who were refractory to a bortezomib- or carfilzomib-containing combination regimen. Methods: This was a phase 1/2, intra-patient, multicenter, open-label trial evaluating the replacement of ixazomib for bortezomib or carfilzomib for MM patients who were refractory in combination with the other agents that the patients had received and failed. Patients received Ixz on days 1, 8 and 15 on a 28-day schedule and the other drugs were administered using the same doses and schedules as they were receiving during their prior regimen. If the Ixz maximum tolerated dose (MTD) for a particular combination regimen was previously determined, then patients were enrolled directly into Phase 2 (PhII). If not, MTD was determined during the Phase 1 (PhI) portion of the trial. Results: To date, a total of 40 patients have been enrolled; 37 patients (21 were enrolled in PhI and 16 in PhII) had completed at least one cycle of this treatment. Patients received a median of 5 prior treatments (range, 1-22). The median follow-up time for all patients was 1.6 months (range, 0.1-10.7 months), whereas that of PhII was 2.2 months (range, 0.2-10.7 months). There was no clinical benefit (CBR; 0%) nor any overall response rate (ORR; 0%) for patients receiving Ixz 3 mg (PhI). Nine patients (43%) showed stable disease (SD) while 12 (57%) exhibited disease progression (PD). In PhII (4mg Ixz) portion of the trial, ORR and CBR were both 18.7% with 16 (43.2%) patients showing SD, and 18 (48.6%) patients displaying PD. Common ≥ Gr3 adverse events were anemia (11%), thrombocytopenia (5.4%), hyponatremia (5.4%), dehydration (5.4%) and neutropenia (2.7%). Conclusions: Replacement of bortezomib or carfilzomib with Ixz infrequently leads to responses among RRMM patient who have progressed while on proteasome inhibitor -containing combination regimens. Clinical trial information: NCT02206425.

Early safety from a phase 1, multicenter, open-label clinical trial of talimogene laherparepvec (T-VEC) injected into liver tumors.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 438-438 ◽  
Author(s):  
J. Randolph Hecht ◽  
Miklos Pless ◽  
Antonio Cubillo ◽  
Aitana Calvo ◽  
Steven Raman ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Liver Tumors ◽  
Disease Incidence ◽  
Phase 1 ◽  
Cell Cancer ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Open Label ◽  
Dose Escalation Study ◽  
Grade 3

438 Background: T-VEC is a genetically modified HSV-1 oncolytic immunotherapy designed to preferentially replicate in tumors, produce GM-CSF, and stimulate anti-tumor immune responses. This study evaluates the safety of intrahepatic injection (inj) of T-VEC in patients (pts) with hepatocellular carcinoma (HCC) or liver metastases (mets). Methods: The primary objective is to assess the maximum tolerated dose. Eligible pts were ≥ 18 years (y) old, had progressive HCC or breast cancer (BC), colorectal cancer (CRC), gastroesophageal cancer, melanoma, non-small cell lung cancer, or renal cell cancer with liver mets, with measurable liver tumors suitable for inj. This dose escalation study comprised 2 groups: A (non-HCC) and B (HCC). T-VEC was given initially at 106 plaque-forming units (PFU)/mL followed by up to 4 mL of 107 PFU/mL (cohort 1) or 108 PFU/mL (cohort 2) every 21 (±3) days (Q21D), or up to 8 mL of the maximum tolerated concentration (MTC) Q21D (cohort 3). Inj volume was based on lesion size. Results: Results from cohorts 1 and 2 of group A are reported. 14 pts were treated; 12 (3 BC, 9 CRC) were DLT-evaluable: Median age was 65.5 y (range: 33, 73); median number of inj was 3; 1 pt received all 12 inj. MTC was 108 PFU/mL. There was 1 DLT, grade 3 aspartate aminotransferase (AST)/grade 2 bilirubin increase (inc), after 1 dose. In all treated pts, 4 (28.6%) had grade 3/4 treatment-related adverse events (TRAEs): anemia and inc gamma-glutamyltransferase, alanine aminotransferase (ALT), and AST. There were 2 deaths attributable to disease. Incidence of serious AEs (SAEs) is shown (Table). Conclusions: The MTC was 108 PFU/mL Q21D after initial inj at 106 PFU/mL. Repeated intrahepatic inj of T-VEC at the FDA-approved concentration for intralesional inj of melanoma was deemed tolerable and feasible in pts with liver mets. Additional investigation in combination with a PD-1 inhibitor is planned. Clinical trial information: NCT02509507. [Table: see text]

Immunotherapy with Y90-radioembolization for metastatic colorectal cancer (iRE-C).

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. TPS276-TPS276
Author(s):  
Pashtoon Murtaza Kasi ◽  
Beau M Toskich ◽  
Chandrikha Chandrasekharan ◽  
Dhivya Prabhakar ◽  
Saima Sharif ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Tumor Microenvironment ◽  
Mismatch Repair ◽  
Checkpoint Inhibitors ◽  
Maximum Tolerated Dose ◽  
Circulating Tumor Dna ◽  
Fixed Dose ◽  
Colorectal Cancers ◽  
Liquid Biopsies ◽  
Open Label

TPS276 Background: Immune checkpoint inhibitors have revolutionized the treatment of a number of cancers. In colorectal cancers, their efficacy is limited to mismatch repair deficient or microsatellite stability-high (dMMR/MSI-High) tumors only. These constitute only 4-5% of all metastatic colorectal cancers (mCRC). Novel approaches are needed to make immunotherapy a viable option for mismatch repair proficient or microsatellite stable (pMMR/MSS) tumors. Increasing exposure of neo-antigens to the immune system could be one potential strategy to enhance the response of immunotherapy. Yttrium 90-radioembolization (Y90-RE) in combination with immunotherapy may work synergistically to enhance efficacy of each other. Additionally, radiation can potentially make the tumor microenvironment conducive to effector T-cell recruitment and function. Therefore, we hypothesize and propose the clinical trial of combining immunotherapy with Y90-RE as a feasible and safe strategy that will improve outcomes in patients with mCRC with liver-predominant metastases. Methods: This clinical trial will be conducted as a single-center, open-label, Phase I/II trial to evaluate initially the feasibility and safety of Y90-RE in combination with a fixed dose of immunotherapy (durvalumab) in subjects with liver-predominant, mCRC (Table). It will be offered in the refractory setting. The trial will be performed in 18 subjects with mCRC with liver metastasis and the safety of immunotherapy (durvalumab) with Y90-RE will be investigated in an accelerated titration design. This would allow a maximum tolerated dose with the minimum number of subjects. Correlative studies pertaining to serial circulating tumor DNA (ctDNA - liquid biopsies) testing as well as immune-panel based profiling will be performed alongside pre- and post-biopsies to study changes in the tumor microenvironment. Clinical trial information: NCT04108481. [Table: see text]

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