A phase I/II study of GB1275, a first-in-class oral CD11b modulator, alone, and combined with pembrolizumab in specified advanced solid tumors or with chemotherapy in metastatic pancreatic cancer (KEYNOTE-A36).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3085-3085
Author(s):  
Drew W. Rasco ◽  
Johanna C. Bendell ◽  
Andrea Wang-Gillam ◽  
Wungki Park ◽  
Eileen Mary O'Reilly ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Phase 1 ◽  
Locally Advanced ◽  
Human Study ◽  
Suppressor Cells ◽  
Elimination Half ◽  
Biomarker Analysis ◽  
Minimal Treatment ◽  
Serial Samples ◽  
Dose Levels

3085 Background: GB1275 is a first-in-class CD11b modulator that reduced myeloid-derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs) at the tumor site, repolarized M2 immunosuppressive TAMs to an M1 phenotype, and increased tumor infiltration of activated CD8+ T cells in preclinical models. When combined with an anti-PD-1 antibody or chemotherapy, these immunomodulatory effects translated into potent anti-tumor effects and prolonged survival in orthotopic PDAC models [Panni RZ, et al. Sci Transl Med. 2019 Jul 3;11(499)]. This ongoing first-in-human study consists of dose escalation of GB1275 monotherapy (Regimen A), GB1275 + pembrolizumab (Regimen B), and GB1275 + nab-paclitaxel + gemcitabine (Regimen C), followed by Phase 2 expansion in newly diagnosed metastatic pancreatic, MSS colorectal, and PD-L1-positive gastric/GEJ cancers. Here we report interim results of the dose escalation portion of the trial. Methods: The dose escalation phase is based on a standard oncology phase 1, 3+3 design. Cohorts of 3 to 6 patients (pts) with histologically confirmed locally advanced/metastatic pancreatic, esophageal, gastric, MSS colorectal, prostate, or breast cancer were sequentially assigned to ascending dose levels of GB1275 taken orally twice daily (BID) in 1 of 3 regimens: Regimen A was initiated first; Regimen B commenced after completion of the first two cohorts of Regimen A, and Regimen C will be initiated when Regimen A is completed. Dose escalation was based on assessment of safety including dose-limiting toxicity (DLT). Serial blood and tumor samples were collected for pharmacokinetic (PK) and biomarker analyses. Results: As of January 21, 2020, 13 pts were treated, with 3 each in Regimen A (GB1275 100mg, 200 mg and 400 mg BID) dose levels and 4 in Regimen B with GB1275 100 mg BID + pembrolizumab. No DLTs have been reported. GB1275 treatment-related adverse events were reported in 5 pts; all were Grade 1 in severity. Preliminary PK analyses showed a mean elimination half-life of ~7 hours. Reduction in peripheral MDSCs was observed in the majority of pts with serial samples. Biomarker analysis in serial tumor tissue is ongoing. Conclusions: Preliminary data show minimal treatment-related toxicities with the studied regimens. PK data support BID dosing. Dose escalation is ongoing. Updated data will be presented. Clinical trial information: NCT04060342 .

scholarly journals A Phase 1 Study of ACTR087 in Combination with Rituximab, in Subjects with Relapsed or Refractory CD20-Positive B-Cell Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 244-244
Author(s):  
Javier Munoz ◽  
Samantha Jaglowski ◽  
Matthew S. McKinney ◽  
Iris Isufi ◽  
Patrick J. Stiff ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antitumor Activity ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
Human Study ◽  
Advisory Board ◽  
Phase 1 Study ◽  
Dose Levels

Background: The Antibody-Coupled T-cell Receptor (ACTR) platform is an autologous engineered T-cell therapy that combines the cell-killing ability of T cells and the tumor-targeting ability of co-administered antibodies to exert potent antitumor immune responses. ACTR087 comprises the extracellular domain of CD16 linked to a CD3ζ-signaling domain and a 4-1BB co-stimulatory domain. Here we present the clinical experience from Study ATTCK-20-2 (NCT02776813), a multicenter, phase 1 study of ACTR087 in combination with rituximab in subjects with relapsed or refractory (R/R) CD20+ NHL. Methods: The main objectives of this first-in-human study were to evaluate the safety and antitumor activity of ACTR087+rituximab. Other objectives included evaluating ACTR T-cell persistence and other correlative biomarkers. Subjects must have had CD20+ NHL that was R/R after prior treatments, which must have included anti-CD20 antibody-containing chemotherapy. Subjects received lymphodepleting chemotherapy (cyclophosphamide and fludarabine) for 3 days, followed by rituximab and a single dose of ACTR087. Additional doses of rituximab were administered q3w until disease progression, unacceptable toxicity, or Investigator decision. The study included a dose escalation phase (increasing doses of ACTR087) and an expansion phase (ACTR087 at the preliminary recommended phase 2 dose [RP2D]); all subjects received rituximab at a fixed dose of 375 mg/m2 q3w. Results: Two dose levels (DL) of ACTR087 were evaluated during dose escalation (n=17). The MTD was exceeded at DL2, with severe cases of cytokine release syndrome (CRS) and neurotoxicity. Statistical analysis of the relationship between non-hematologic toxicity and ACTR+ T-cell doses was retrospectively performed (two-parameter Bayesian logistic regression model) to estimate an RP2D of 35×106 ACTR+ T cells. Nine subjects enrolled in an expansion cohort and received ACTR087 at this RP2D in combination with rituximab. Among all subjects treated (n=26), the majority (69%) were diagnosed with DLBCL. Subjects had received a median of 3 (range 1-9) prior lines of therapy, with 77% having received ≥3 prior lines. ACTR087 showed dose-dependent expansion with peak levels generally observed 7 to 14 days post administration. In subjects with ongoing clinical response (CR), ACTR remained detectable through the last timepoint evaluated. Across all cohorts, Grade ≥3 TEAEs reported in >3 subjects regardless of causality were limited to hematologic events. Potential T cell-mediated toxicities were observed, including 4 serious cases of CRS (Gr 4 in 2 subjects, both with fatal sepsis) and 2 serious cases of neurotoxicity (1 Gr 5, 1 Gr 4 in a subject with fatal septic shock). Elevated baseline inflammatory markers (eg, ferritin, CRP) were observed in patients who developed Gr ≥3 CRS and neurotoxicity post ACTR087. Of note, severe CRS presented without fever and events occurred >7 days post ACTR087. Clinical activity was reported with an ORR of 50% in all dose levels tested, including durable complete responses, with one subject in CR for 869+ days (Table 1). Conclusions: ACTR087+rituximab demonstrated antitumor activity, with observed safety events that are expected with other autologous T-cell products. The time to onset and clinical presentation of severe CRS and neurotoxicity events in this study informed the safety monitoring and adverse reaction management guidance across clinical studies of ACTR T-cell products. Data from this first-in-human study of ACTR087+rituximab confirm the proof of concept and will be used to guide further development for the ACTR platform. Updated clinical data, as well as expanded biomarker correlations to efficacy and safety, will be presented. Disclosures Munoz: Pharmacyclics /Janssen: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy; Fosunkite: Speakers Bureau; AstraZeneca: Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene/Juno: Consultancy, Research Funding; Genentech: Consultancy, Research Funding, Speakers Bureau; Kite/Gilead: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy; Alexion: Consultancy; Portola: Research Funding; Incyte: Research Funding; Bayer: Consultancy, Speakers Bureau; Merck: Consultancy. Jaglowski:Kite: Consultancy, Other: advisory board, Research Funding; Novartis: Consultancy, Other: advisory board, Research Funding; Unum Therapeutics Inc.: Research Funding; Juno: Consultancy, Other: advisory board. Isufi:Celgene: Consultancy; Novartis: Consultancy; Astra Zeneca: Consultancy. Stiff:Gamida-Cell: Research Funding; Incyte: Research Funding; Cellectar: Research Funding; Unum: Research Funding; Gilead/Kite Pharma: Consultancy, Honoraria, Research Funding; Amgen: Research Funding. Sachs:Unum Therapeutics Inc.: Employment. Ranger:Unum Therapeutics Inc.: Employment. Harris:Unum Therapeutics Inc.: Employment. Payumo:Unum Therapeutics Inc.: Employment. Akard:Bristol-Myers Squibb: Speakers Bureau; Gilead: Speakers Bureau; Takeda: Speakers Bureau; Novartis: Speakers Bureau; Celgene: Speakers Bureau.

Phase 1 dose-escalation study of ACT001 in patients with recurrent glioblastoma and other advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2037-2037
Author(s):  
Jason D. Lickliter ◽  
Ross Jennens ◽  
Charlotte Rose Lemech ◽  
Ganessan Kichenadasse ◽  
Dongpo Cai ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Radiation Treatment ◽  
Phase 1 ◽  
Dose Range ◽  
Malignant Gliomas ◽  
Advanced Solid Tumors ◽  
Biomarker Analysis ◽  
Dose Levels

2037 Background: ACT001, an orally-available parthenolide derivative targeting NF-κB and STAT3 signaling pathways, has immunomodulatory effects and showed promising activity in preclinical models of glioblastoma (GBM). The updated data in this report summarizes clinical findings from this first-in-human clinical trial of ACT001 in patients with advanced solid tumors, including GBM. Methods: Eligible patients were adults with ECOG PS 0-1 and satisfactory hematologic, renal and hepatic function. Additionally, GBM patients had progressive disease despite initial radiation and temozolomide, measurable tumor and no radiation treatment within 3 months prior to enrollment. ACT001 was given orally BID until intolerance or disease progression. Dose escalation followed a standard 3+3 design. Gliomas were imaged with MRI every 8 weeks and responses assessed using RANO criteria. Results: A total of 24 patients were enrolled as of this report: 14 with primary GBM, 2 with secondary GBM, 2 with anaplastic astrocytoma, 2 with colorectal cancer and 1 with each of anaplastic oligioastrocytoma, diffuse intrinsic pontine glioma, non-small cell lung cancer and pleural epithelioid mesothelioma. Median age was 49 years old (range 32-72). ACT001 dose levels were 100 mg BID, 200 mg BID, 400 mg BID, 600 mg BID, 900 mg BID and 1200 mg BID. Study drug treatment was well tolerated with no dose-limiting toxicity or ACT001-related SAE observed. The originally-planned maximum dose of 600 mg BID and the 1200 mg BID dose were expanded to 7 and 5 patients, respectively. The plasma half life of ACT001 was approximately 3-4 hours and no accumulation was observed after multiple dosing. Cmax and AUC0-last were approximately dose linear across the evaluated dose range. Of the 19 patients with recurrent malignant gliomas, a complete remission was observed in 1 patient with GBM (ongoing 27 months from starting ACT001) and stable disease lasting ≥ 6 months was seen in 3 patients. Preliminary biomarker analysis of PBMC samples revealed a post-treatment reduction in CD4+ Treg cells at some dose levels. Conclusions: In this first-in-human phase 1 study, ACT001 was well tolerated and showed satisfactory bioavailability and preliminary evidence of anti-tumor activity in malignant glioma patients dosed at 400 mg BID or lower. A phase 1b trial in recurrent GBM patients of ACT001 at 200-400 mg BID in combination with anti-PD-1 therapy is planned. Clinical trial information: ACTRN12616000228482.

A first in-human study of A166 in patients with locally advanced/metastatic solid tumors which are HER2-positive or HER2-amplified who did not respond or stopped responding to approved therapies.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1049-1049
Author(s):  
Yongheng Liu ◽  
Wei Lian ◽  
Xi Zhao ◽  
Wei Qi ◽  
Jian Xu ◽  
...  
Keyword(s):  
Dose Level ◽  
Phase 1 ◽  
Locally Advanced ◽  
Human Study ◽  
Study Drug ◽  
Antibody Drug Conjugate ◽  
Her2 Positive ◽  
Open Label ◽  
Best Response ◽  
Dose Levels

1049 Background: HER2 is an effective therapeutic target for breast and gastric cancer. A166 is an antibody-drug conjugate composed of a novel cytotoxic drug site-specifically conjugated to transtuzumab sequence via a stable protease-cleavable valine citrulline linker. Methods: This was a single arm, open-label, multicenter, dose escalating Phase 1 first-in-human study of A166 as monotherapy in solid tumor patients. Dose escalation and MTD identification was directed using a Bayesian logistic regression model with overdose control. The following dose levels were evaluated in this study: 0.3, 1.2, 3.6, 4.8 mg/kg. (ClinicalTrials.gov NCT03602079) Results: As of November 1, 2019 35 pts have completed the DLT evaluation period across 4 dose levels. Overall, A166 had an acceptable toxicity profile with no unexpected toxicities related to the study drug. No adverse events recorded met the protocol specified definition of a dose limiting toxicity at any studied dose level. Most frequently (≥10%) occurring TEAEs include were Keratitis, Decreased appetite, Dry eye, Vision blurred etc. Overall incidence of ophthalmic toxicities in the 3.6 mg/kg cohort was 80% and in the 4.8 mg/kg cohort it was 83%. Among the 27 patients evaluable for efficacy, best response was progression of disease in 11 patients (41%), stable disease in 9 patients (33%) and partial response in 7 patients (26%), for the total disease control rate of 59%.Responses were seen only at the dose levels of 3.6 mg/kg and 4.8 mg/kg. Conclusions: A166 demonstrated clinically meaningful efficacy in heavily pretreated patients with relapsed or refractory advanced solid cancers. The achievement of an ORR of 36% at efficacious dose levels and up to 100% in HER2 positive patients regardless of histology (2 CRC, 1 BC and 1 NSCLC) at the highest studied dose level exceed Clinical trial information: NCT03602079 .

Clinical Safety and Activity in a Phase 1 Trial of IPI-145, a Potent Inhibitor of Phosphoinositide-3-Kinase-δ,γ, in Patients with Advanced Hematologic Malignancies

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3663-3663 ◽  
Author(s):  
Ian W. Flinn ◽  
Steven M. Horwitz ◽  
Manish Patel ◽  
Anas Younes ◽  
James R. Porter ◽  
...  
Keyword(s):  
T Cell ◽  
Dose Escalation ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Hematologic Malignancies ◽  
Lymphocytic Leukemia ◽  
Grade 3 ◽  
Expansion Cohort ◽  
Dose Levels

Abstract Abstract 3663 Introduction: Phosphoinositide-3-kinases (PI3Ks) play pivotal roles in cell signaling and regulate a variety of cellular functions relevant to oncogenesis. Impaired development and function of B and T lymphocytes has been demonstrated in PI3K-δ and PI3K-γ isoform knockout mice, supporting the development of PI3K-δ,γ specific inhibitors for B- and T-cell lymphoid malignancies. IPI-145 is a potent PI3K-δ,γ inhibitor in clinical development for patients (pts) with hematologic malignancies. The activity of IPI-145 via PI3K-δ and PI3K-γ isoform inhibition has been characterized in biochemical and cellular assays and demonstrated in preclinical models of B- and T-cell mediated disease. Early results of the Phase 1 study in pts with advanced hematologic malignancies are reported here. Methods and Patients: This Phase 1 dose-escalation study is designed to evaluate the safety, pharmacokinetics (PK) and activity of orally administered IPI-145 in pts with advanced hematologic malignancies, including T-cell lymphomas/leukemias. Sequential cohorts of pts are enrolled at progressively higher dose levels with expansion cohorts of pts with select hematologic malignancies. IPI-145 is administered orally 2 times per day (BID) continuously in 28-day cycles. Tumor response is evaluated based on disease-specific standard criteria. Results: As of 16 July 2012, the study had enrolled 20 pts; 5 pts with chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL), 4 with indolent non-Hodgkin's lymphoma (iNHL), 3 with aggressive B-cell NHL [including diffuse large B-cell lymphoma (DLBCL) n=2 and Richter's transformation n=1], 3 with multiple myeloma (MM), 2 with Hodgkin's lymphoma (HL), 2 with T-cell lymphoma [anaplastic large-cell lymphoma (ALCL) n=2] and 1 with mantle cell lymphoma (MCL). Of these pts, 11 are male and 9 female, with a median [range] age of 63 years [30–81], with 36% <6 month from most recent prior systemic therapy. The median [range] number of prior therapies was 3 [1–8]. IPI-145 doses administered include 8 mg BID (n=1), 15 mg BID (n=6), 25 mg BID (n=7), 35 mg BID (n=3), and 50 mg BID (n=3). The median [range] number of treatment cycles was 2 [1–8], with 12 (60%) pts continuing on treatment. Adverse events (AEs) have occurred in 13 (65%) pts, including 7 (35%) pts with AEs Grade ≥3. Treatment-related AEs occurred in 11 pts (55%) with Grade ≥3 occurring in 5 pts (25%). Grade 4 neutropenia was the one dose limiting toxicity observed to date (15 mg dose cohort). New Grade ≥3 hematological laboratory abnormalities included neutropenia [n= 6 (30%)] and thrombocytopenia [n= 1 (5%)]. Grade 3 ALT/AST elevations occurred in 1 (5%) MM pt with onset 6 weeks after IPI-145 initiation. Preliminary PK show dose-proportional increases in plasma Cmax and AUC over the dose range studied. Further, the PK and initial pharmacodynamic (PD) data from the first 3 cohorts (8–25 mg BID) predict continuous suppression of the PI3K-δ pathway with increasing inhibition of the PI3K-γ pathway with a 25 mg BID dose or greater. In the evaluable pts (n=11), responses were observed at the 8, 15, and 25 mg BID dose levels including 2/3 CLL/SLL pts (0 CR/2 PR/1 SD), 1/2 iNHL pts (1 CR/0 PR/1 SD), and 1/1 in MCL (1 PR). No responses have been observed to date in evaluable pts with MM (0/3) or aggressive NHL (0/2). All pts with at least SD after 2 cycles (n=6) remain on treatment including the first pt dosed. Based on the PK/PD and the preliminary activity observed in pts with CLL, iNHL and MCL, an expansion cohort is enrolling pts in these select hematologic diseases dosed at 25 mg BID to further evaluate the safety and preliminary activity of IPI-145. Dose escalation continues with a focus on pts with T-cell malignancies and DLBCL where increasing suppression of the PI3K-γ isoform may improve the efficacy profile. Additional expansion cohorts in T-cell lymphoma, DLBCL, myeloproliferative neoplasms and the acute leukemias will better define disease specific activity. Conclusions: IPI-145, an oral, potent PI3K-δ,γ inhibitor, appears to be well tolerated and has shown initial clinical activity in pts with iNHL, MCL, and CLL. A dose of 25 mg BID effectively inhibits PI3K-δ, providing a rationale for expansion in CLL/iNHL/MCL. Additional safety and efficacy data from the ongoing dose escalation evaluation in T-cell/aggressive NHL and the CLL/iNHL/MCL expansion cohort will be presented. Disclosures: Flinn: Infinity Pharmaceuticals, Inc.: Research Funding. Horwitz:Seattle Genetics: Consultancy, Research Funding; Allos: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Genzyme: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy; Johnson & Johnson: Consultancy; Infinity Pharmaceuticals, Inc. : Research Funding. Patel:Infinity Pharmaceuticals, Inc. : Research Funding. Younes:Novartis: Honoraria, Research Funding; Celgene: Honoraria; Seattle Genetics: Honoraria, Research Funding; Sanofi-Aventis: Honoraria, Research Funding; MIllenium: Honoraria; Incyte: Honoraria; Genentech: Research Funding; Infinity Pharmaceuticals, Inc. : Research Funding; Gilead: Research Funding. Porter:Infinity Pharmaceuticals, Inc. : Employment. Sweeney:Infinity Pharmaceuticals, Inc. : Employment. Allen:Infinity Pharmaceuticals, Inc. : Employment. Kelly:Infinity Pharmaceuticals, Inc. : Employment. Kahl:Infinity Pharmaceuticals, Inc. : Research Funding.

A NKG2D-based CAR-T therapy in a multinational phase I dose escalation and expansion study targeting multiple solid and hematologic tumor types.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS3093-TPS3093 ◽  
Author(s):  
Bikash Verma ◽  
Philippe Georges Aftimos ◽  
Ahmad Awada ◽  
Jean-Pascal H. Machiels ◽  
Jason B. Brayer ◽  
...  
Keyword(s):  
Phase I ◽  
Tumor Cells ◽  
Dose Escalation ◽  
Phase 1 ◽  
Locally Advanced ◽  
Conditioning Regimen ◽  
Target Antigen ◽  
Clinical Activity ◽  
Car T ◽  
Tumor Types

TPS3093 Background: Chimeric Antigen Receptor (CAR)-T therapy has potentially serious limitations related to target antigen loss, toxicity due to pre-conditioning regimen, and lack of activity in many tumor types. To overcome these limitations, we have developed a novel CAR-T, called NKR-2, incorporating the full-length human natural killer receptor NKG2D fused with the human CD3 zeta signaling domain. When expressed in T-cells, the naturally-expressed DAP10 provides co-stimulatory signals to NKR-2 to produce cytokines and selectively target tumor cells upon recognition of up to 8 different stress-induced NKG2D ligands expressed in many solid and hematologic malignancies. In preclinical studies, NKR-2 demonstrated long-term anti-tumor activity towards a breadth of tumor indications, in the absence of pre-conditioning, whilst simultaneously targeting tumor cells and cells from the local tumor neo-vasculature and suppressive immune environment. In our recently completed First-in-Human Phase 1 study (NCT02203825) in hematologic cancers, a single administration of autologous NKR-2 was safe with initial signs of clinical benefit. Methods: Exploiting the multiple ligand targeting capability and unique mode of action of NKR-2, the THINK trial (THerapeutic Immunotherapy with NKR-2) is an open-label Phase I study that will assess the safety and clinical activity of multiple infusion NKR-2 treatment (every 2 weeks x 3 infusions) in relapse/refractory patients with metastatic or locally advanced CRC, urothelial carcinoma, TNBC, pancreatic cancer, recurrent epithelial ovarian and fallopian tube carcinoma, AML/MDS and MM, post standard treatment. The study contains two consecutive segments. The dose escalation segment will enroll 18 patients in two separate hematologic and solid malignancy arms, and will evaluate 3 dose levels of NKR-2 (3x108, 1x109 and 3x109 per injection) following a 3+3 design. The expansion segment will then enroll 96 additional patients in 7 separate cohorts for each indication with 3 steps of statistical analysis (overall futility, cohort futility and final evaluation). The study is open for recruitment in both EU and US. Clinical trial information: NCT03018405.

An open label, multicenter, phase I/II study of RP1 as a single agent and in combination with PD1 blockade in patients with solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS2671-TPS2671
Author(s):  
Mark R. Middleton ◽  
Joseph J. Sacco ◽  
Jaime R. Merchan ◽  
Brendan D. Curti ◽  
Ari M. Vanderwalde ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Objective Response ◽  
Phase 2 ◽  
Biomarker Analysis ◽  
Tumor Types

TPS2671 Background: RP1 is an attenuated oncolytic HSV-1 that expresses a fusogenic glycoprotein from gibbon ape leukemia virus (GALV-GP R-) and GM-CSF. RP1 induces potent GALV-GP R- enhanced immunogenic cell death and host anti-tumor immunity in murine tumor models and increases PD-L1 expression. This clinical trial (NCT03767348) was designed to test the hypotheses that RP1 is safe when given alone and together with nivolumab (phase 1) and has efficacy together with nivolumab in four tumor types (phase 2). Methods: The primary goals of this clinical trial in a total of ~150 patients are to define the safety profile of RP1 alone and together with nivolumab, determine the recommended phase 2 dose (phase 1), and then in four phase 2 cohorts, to determine objective response rate in patients with melanoma, non-melanoma skin cancer, urothelial carcinoma and MSI-H solid tumors. Secondary objectives include duration of response, CR rate, PFS, viral shedding, and immune biomarker analysis. Patients with advanced cancer who failed prior therapy were eligible for the phase I component. In Phase 2 patients with histologic diagnoses of the four tumor types (N=30 for each) and who meet safety criteria for nivolumab treatment are eligible. Prior treatment with checkpoint blockade is not allowed except for the melanoma cohort. In the phase 1 portion patients are treated by intra-patient dose escalation of virus (range, 104 - 108 PFU) by intratumoral injection every two weeks for 5 total doses followed by 12 patients dosed 8 times at the RP2D in combination with nivolumab. Phase 1 patients were divided into two groups based on presence of clinically accessible lesions amenable to direct injection or those with visceral/deep lesions requiring image guidance for injection. In the phase 2 portion patients will receive the RP2D for eight injections and nivolumab will be given starting with the second RP1 injection. For the phase 1 portion, a modified 3+3 dose escalation design is used to assess safety and in the phase 2 portion, statistical analysis will be performed using a two-stage three-outcome optimum design with objective responses determined by RECIST criteria. As of February 11, 2019, 27 patients have been enrolled. Clinical trial information: NCT03767348.

First-in-human study of palcitoclax (APG-1252), a novel dual Bcl-2/Bcl-xL inhibitor, demonstrated advantages in platelet safety while maintaining anticancer effect in U.S. patients with metastatic solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3509-3509
Author(s):  
Nehal J. Lakhani ◽  
Drew W. Rasco ◽  
Qi Zeng ◽  
Yuefen Tang ◽  
ZHIYAN LIANG ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Human Study ◽  
Maximum Tolerated Dose ◽  
Neuroendocrine Prostate Cancer ◽  
Important Approach ◽  
Expansion Stage ◽  
Further Development ◽  
Clinical Trial Information

3509 Background: Targeting Bcl-2/Bcl-xL proteins is considered as an important approach for anticancer drug development. Palcitoclax (APG-1252) was being developed to reduce on-target platelet toxicity without diminishing antitumor potency. Methods: The phase 1 study was to evaluate the safety/tolerability, pharmacokinetics (PK), and preliminary efficacy (assessed per RECIST 1.1) of palcitoclax in US patients with metastatic small-cell lung cancer (SCLC) or other solid tumors (NCT03080311). A standard “3+3” design was applied to the dose-escalation stage. Palcitoclax was administered IV infusion for 30 minutes, twice a week (BIW) or once a week (QW) for 3 weeks in a 28-day cycle. Once the maximum tolerated dose / recommended phase 2 dose (MTD/RP2D) was determined, additional patients were treated in a dose-expansion stage. Results: The dose-escalation phase has been completed with 42 patients (31 on BIW and 11 on QW) who received palcitoclax at 8 dose cohorts ranging 10 mg - 400 mg. Most adverse events (AEs) were grade 1 or 2 (G1 or G2), and 26.2% patients had ≥ G3 TRAEs. The most common TRAEs were platelet count decreased (14.3%), aspartate aminotransferase increased (9.5%), and alanine aminotransferase increased (7.1%). Rapid platelet drop was observed in patients treated at 320 mg and 400 mg, which was transient and resolved rapidly within 2-6 days. Palcitoclax at 240 mg once weekly was determined to be MTD/RP2D. Of 36 efficacy-evaluable patients, 3 patients with SCLC, neuroendocrine prostate cancer, and ovarian cancer respectively achieved partial response (PR) and 8 patients had stable disease (SD) as their best overall response. One patient with SCLC had a PR that lasted over 21 cycles. Preliminary PK analyses showed that Cmax and AUC were approximately dose proportional over the range of 10 mg to 320 mg following the IV infusion on Day 1, with a mean T1/2 of 3.0-13.0 hours. Conclusions: Palcitoclax is safe and well tolerated, with a favorable platelet toxicity profile. Its promising antitumor effect supports its further development in combination therapies for treatment of patients with SCLC and other solid tumors. Clinical trial information: NCT03080311 .

CSF1R inhibition with emactuzumab in locally advanced diffuse-type tenosynovial giant cell tumours of the soft tissue: a dose-escalation and dose-expansion phase 1 study

2015 ◽  
Vol 16 (8) ◽  
pp. 949-956 ◽  
Author(s):  
Philippe A Cassier ◽  
Antoine Italiano ◽  
Carlos A Gomez-Roca ◽  
Christophe Le Tourneau ◽  
Maud Toulmonde ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Giant Cell ◽  
Dose Escalation ◽  
Phase 1 ◽  
Locally Advanced ◽  
Diffuse Type ◽  
Phase 1 Study ◽  
Expansion Phase ◽  
Giant Cell Tumours

scholarly journals MM-004: A Phase 1, Dose-Escalation Study to Determine the Maximum Tolerated Dose, Safety, Efficacy, and Pharmacokinetics of Pomalidomide Alone or in Combination with Dexamethasone in Patients with Refractory or Relapsed and Refractory Multiple Myeloma in Japan

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2107-2107
Author(s):  
Shinsuke Iida ◽  
Hiromi Iwasaki ◽  
Takaaki Chou ◽  
Kensei Tobonai ◽  
Kazutaka Sunami ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Single Dose ◽  
Plasma Concentration ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
Dose Escalation Study ◽  
Refractory Multiple Myeloma ◽  
Multiple Doses ◽  
Dose Levels

Abstract Background: Patients (pts) with refractory or relapsed and refractory multiple myeloma (RRMM) who have exhausted treatment (Tx) with lenalidomide (LEN) or thalidomide (THAL) and bortezomib (BORT) have shortened overall survival (OS; Kumar, Leukemia, 2012). Pomalidomide (POM) is a novel oral IMiDs® immunomodulatory agent with direct antimyeloma and stromal cell inhibitory effects (Quach, Leukemia, 2010; Mark, Leuk Res, 2014). POM 4 mg (± dexamethasone) is approved in some countries for Tx of pts with RRMM based on phase 3 results showing significant improvement vs high-dose dexamethasone in response, progression-free survival (PFS), and OS and phase 1/2 results showing high and durable overall response rates (ORRs; Richardson, Blood, 2013; Richardson, Blood, 2014; San Miguel, Lancet Oncol, 2013). MM-004 is a phase 1, open-label, dose-escalation study designed to assess the tolerated dose (TD), safety, efficacy, and pharmacokinetics (PK) of POM alone or POM + low-dose dexamethasone (LoDEX) in Japanese pts with RRMM. Methods: Pts must have been ≥ 20 yrs old with a documented diagnosis of MM, have had ≥ 2 prior lines of anti-MM Tx including ≥ 2 cycles of LEN and BORT (alone or in combination), and have RRMM defined as progressive disease (PD) during or within 60 days of completing their last anti-MM Tx. Tx consisted of POM 2 mg (Cohort 1) or 4 mg (Cohort 2) day (D) 1-21 of a 28-D cycle and DEX 40 mg (20 mg for pts > 75 yrs) D1, 8, 15, and 22 (starting on cycle 2). Tx was continued until PD, unacceptable adverse event (AE), or voluntary withdrawal. Pts enrolled in Cohort 1 received a single dose of POM 0.5 mg at D7 for PK evaluation. The primary endpoint was TD; secondary endpoints included ORR based on International Myeloma Working Group criteria, objective response, duration of response (DOR), PFS, PK, and safety. Results: Twelve pts were enrolled (6 in each cohort); 2 pts remain on Tx as of June 27, 2014 (Cohort 2, n= 2). Median age was 68 yrs (range, 52-76 yrs); 75% of pts were aged > 65 yrs. Median number of prior anti-MM Tx was 6 (range, 4-10) and baseline creatinine clearance (CrCl) was ≥ 60 mL/min for all pts except one. Six pts received prior THAL-based Tx (Cohort 1, n= 3; Cohort 2, n= 3). TD was determined to be POM 4 mg D1-21 of a 28-D cycle (a dose-limiting toxicity of grade 4 neutropenia for ≥ 7 days was observed in 1 pt in cohort 1). This result showed that the TD of POM in Japanese pts with MM was the same as that in Caucasian pts with MM. Median duration of treatment was 6.5 cycles in all pts. The best ORR (≥ partial response [PR]) was 25% (3/12 pts) across both cohorts; ORR was 17% (1/6) in Cohort 1 and 33% (2/6) in Cohort 2. Overall median PFS was 5.5 months (5.1 months in Cohort 1; not reached in Cohort 2). Maximum POM plasma concentration (Cmax) was 9.1, 35.6, and 70.2 ng/mL after single dose of POM 0.5, 2, and 4 mg, respectively, and was reached at times ranging from 0.9 to 6 h. Cmax was 37.6 and 71.2 ng/mL after multiple doses of POM 2 and 4 mg. Systemic POM exposure as measured by geometric means of area under the plasma concentration time curve (AUC) was 84.9, 364.4, and 685.7 ng•h /mL after a single doses of POM 0.5, 2, and 4 mg, respectively. AUC was 411.5 and 713.8 ng•h /mL after multiple doses of POM 2 mg and 4 mg. Both Cmax and AUC exposures increased in a dose-proportional manner from 0.5 to 4 mg, as assessed by both visual inspection and statistical analysis. Clearance and volume of distribution were similar across dose levels. The mean half-life (t1/2) of POM was comparable across dose levels, with t1/2 of approximately 6.4, 6.9, and 6 h after single doses of POM 0.5, 2, and 4 mg, respectively. After multiple doses of POM 2 mg and 4 mg, t1/2was approximately 7.3 and 5.5 h. Grade ≥ 3 AEs occurred in 11 pts (92%), and the most frequently reported AE was neutropenia (8 pts, 67%). Other frequently reported AEs (all grades) were thrombocytopenia, anemia, leukopenia, and peripheral edema. Conclusions: POM 4 mg was identified as the TD in Japanese pts with RRMM, which is consistent with previous findings in Caucasian pts with MM. However, pts should be monitored for the known AE profile of POM and managed appropriately. The combination of POM with LoDEX was also found to be tolerable in Japanese pts with RRMM. Systemic exposure to POM increased dose proportionally, and limited drug accumulation was observed following multiple doses. Responses (≥ PR) were observed in 25% of pts. Further investigation of the efficacy and safety of POM + LoDEX in Japanese pts with RRMM in a phase 2 trial is warranted. Disclosures Iida: Celgene Corp: Honoraria, Research Funding. Tobonai:Ono: Research Funding; Lilly: Research Funding; Janssen: Research Funding; Celgene Corporation: Research Funding. Sunami:Celgene Corp: Honoraria. Kurihara:Celgene Corporation: Employment. Midorikawa:Celgene: Employment. Zaki:Celgene : Employment, Equity Ownership. Doerr:Celgene Corp: Employment.

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