A phase I trial combining plinabulin and nivolumab for metastatic NSCLC: Trial in progress.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. TPS128-TPS128
Author(s):  
Nicolas Villanueva ◽  
Klarissa Son ◽  
Shihfan Yeh ◽  
Sonia Jain ◽  
Elaine Eng ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Clinical Studies ◽  
Phase I Trial ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Open Label ◽  
Antibody Treatment ◽  
Metastatic Nsclc

TPS128 Background: Plinabulin (Plin) is a microtubule-destabilizing agent (MDA) that inhibits the polymerization of tubulin monomers and leads to disruption of the tumor vasculature. It has been shown in clinical studies of advanced NSCLC to produce a significantly longer duration of response when combined with docetaxel versus docetaxel alone (NCT00630110). MDAs were also shown to trigger the maturation of dendritic cells and the production of pro-inflammatory cytokines, thereby enhancing T-cell proliferation. Pre-clinical studies have shown that MDAs in combination with immune checkpoint inhibitors (ICI) demonstrated a superior response rate and survival when compared to ICI alone. Nivolumab is an anti-PD-1 antibody that is FDA approved for previously treated metastatic NSCLC regardless of PD-L1 expression. We hypothesized that the combination of Plin and Nivolumab will enhance the immune response, resulting in a higher response rate and longer overall survival. Methods: This is an open label single center phase I trial. The Dose Escalation Portion (Part 1) employs a 3+3 design with dose escalation of Plin starting at 13.5mg/m2 (biologically effective dose as single agent), combined with the FDA approved dose of Nivolumab 240mg. Plin is given on days 1,8, and 15 of 28- day cycles and Nivolumab is given on days 1 and 15. The dose of Plin will be escalated to 20mg/m2, 30 mg/m2, and 40mg/m2 until the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) is determined. The Expansion Cohort (Part 2) will enroll 20 patients with NSCLC to be treated at the RP2D, including the patients who will have received this dose in Part 1. Treatment will continue until disease progression, development of unacceptable toxicity, or a protocol-defined reason for discontinuation. Eligible patients include metastatic NSCLC who have failed platinum-based doublet and regardless of prior anti-PD-1/PD-L1 antibody treatment. Part 1 is enrolling in an expanded cohort 2 due to one dose-limiting toxicity (DLT) in this group. Clinical trial information: NCT02812667.

A phase I trial evaluating NBTXR3 activated by radiotherapy in combination with nivolumab or pembrolizumab in patients with advanced cancers.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2590-2590
Author(s):  
Colette Shen ◽  
Jessica M. Frakes ◽  
Jiaxin Niu ◽  
Ari Rosenberg ◽  
Jared Weiss ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Tumor Regression ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Kidney Injury ◽  
Complete Response ◽  
Intratumoral Injection ◽  
Primary Objective ◽  
Open Label

2590 Background: Immune checkpoint inhibitors (ICIs) targeting PD-1 are an effective treatment for a variety of cancers. However, the majority of patients (pts) exhibit resistance to ICIs. Overcoming this resistance represents a major challenge in immuno-oncology. Emerging evidence suggests radiation therapy (RT) produces an immunomodulatory effect that may act synergistically with ICIs. However, RT dose and ultimate efficacy are limited by toxicity to surrounding healthy tissues. NBTXR3, a novel radioenhancer administered by direct intratumoral injection (ITI), is designed at the nanoscale to increase RT dose deposit within tumor cells and subsequent tumor cell killing, without increasing toxicity to surrounding healthy tissue. Preclinical data suggest NBTXR3/RT can trigger a local and systemic anti-tumor immune response and overcome anti-PD-1 resistance. NBTXR3/RT combined with anti-PD-1 may prime the immune system to increase the proportion of ICI responders, or convert ICI non-responders to responders. Methods: This is a multicenter, open-label, phase I trial [NCT03589339] to evaluate NBTXR3/RT/anti-PD-1 in 3 cohorts: (1) Locoregional recurrent or recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) amenable to HN re-irradiation, and metastases from any primary cancer eligible for anti-PD-1 (nivolumab or pembrolizumab) treatment specifically localized in the lung (2) or liver (3), respectively. Stereotactic body RT (SBRT) is delivered at tumor-site selective doses per standard practice. The primary objective is NBTXR3/RT/anti-PD-1 recommended phase 2 dose in each cohort. Secondary objectives are anti-tumor response (objective response rate), safety and feasibility of NBTXR3 injection. Results: Nine pts have been treated: 3 HNSCC, 4 lung, 2 liver. 7/9 pts were anti-PD-1 non-responders. Overall tumor regression was observed in 8/9 pts. NBTXR3/RT/anti-PD-1 resulted in tumor regression in 6/7 pts who had progressed on prior anti-PD-1. A complete response in the injected lymph node lasting over 1 year was observed in 1 anti-PD-1 naïve pt. 2 SAEs related to anti-PD-1 and possibly related to NBTXR3 (G5 pneumonitis, G4 hyperglycemia) were observed in 1 anti-PD-1 naïve HNSCC pt and considered DLTs. This pt also experienced 2 other SAEs related to anti-PD-1 (G4 diabetic ketoacidosis, G4 acute kidney injury). SBRT-related safety profile was as expected. Updated results will be presented. Conclusions: Data from this first-in-human phase I trial evaluating NBTXR3/RT/anti-PD-1 in pts with advanced cancers, show NBTXR3 ITI is feasible and well-tolerated. NBTXR3/RT/anti-PD-1 demonstrated promising signs of efficacy. Of particular interest, NBTXR3/RT can overcome ICI resistance in pts having progressed on prior anti-PD-1, supporting further development of NBTXR3 in combination with anti-PD-1 as well as other ICIs. Clinical trial information: NCT03589339.

A Multicenter Phase I/II Dose Escalation Study of Lenalidomide in Combination with Melphalan and Dexamethasone in Subjects with Newly-Diagnosed Light-Chain (AL)-Amyloidosis.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1732-1732
Author(s):  
Philippe Moreau ◽  
Arnaud Jaccard ◽  
Lotfi Benboubker ◽  
Bruno Royer ◽  
Valerie Coiteux ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Response Rate ◽  
Standard Dose ◽  
High Dose ◽  
Al Amyloidosis ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Open Label ◽  
Dose Escalation Study

Abstract A recent prospective randomized trial comparing standard-dose to high-dose melphalan in patients presenting with newly diagnosed AL-amyloidosis showed that oral melphalan-dexamethasone (M-dex) given monthly could be considered the current standard of care, with a median survival of 56 months (Jaccard, N Engl J Med 2007). The use of a combination of lenalidomide and dexamethasone has also been tested in patients with symptomatic AL-amyloidosis. The initial dose of lenalidomide at 25 mg/day was poorly tolerated. However, a 15 mg/day dose regimen was well tolerated and effective, with both hematologic and organ responses (Dispenzieri, Blood 2007 & Sanchorawala, Blood 2007). Combining M-dex with lenalidomide (M-dex-rev) could increase the response rate but the toxicity of this regimen is still unknown. Thus we have initiated a multicenter single-arm open-label phase I/II dose escalation study of lenalidomide administered in combination with M-dex. The primary endpoint was the incidence of dose limiting toxicities (DLT) during the first cycle of lenalidomide at a given dose level in order to determine the maximum tolerated dose (MTD). In addition to melphalan 0.18mg/kg/day from day 1–4 of each 28 day cycle and dexamethasone 40mg/day from day 1– 4 of each 28 day cycle, 3 cohorts of 3 subjects were successively exposed to escalating doses of lenalidomide (5, 10 and 15mg once daily on days 1–21 of a 28 day cycle). DLT was defined using National Cancer Institute (NCI) common toxicity criteria during the first 4 weeks of treatment (one cycle) as the following: at least grade 2 cardiac arrhythmia, at least grade 3 non hematologic toxicity, grade 4 neutropenia lasting >7 days or any other Grade 4 hematologic toxicity, or treatment delay due to toxicity that occurred during the first cycle. No DLT was observed among the first 3 patients treated at 5, 10 and 15 mg lenalidomide/day. 9 additional subjects will be enrolled at 15 mg/day to better define the safety profile and estimate the hematologic and organ response rate. Final results regarding both toxicity and efficacy will be presented during the meeting.

Phase I/II dose escalation and expansion study of FLX475 alone and in combination with pembrolizumab in advanced cancer.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. TPS24-TPS24
Author(s):  
William Ho ◽  
Nicole Nasrah ◽  
Dan Johnson
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
Dose Escalation ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Single Agent ◽  
Safety Data ◽  
Receptor Occupancy ◽  
Open Label ◽  
Ligand Expression

TPS24 Background: Regulatory T cells (Treg) can dampen anti-tumor immune responses in the tumor microenvironment (TME). The predominant chemokine receptor on human Treg is CCR4, the receptor for the chemokines CCL17 and CCL22, which are produced by tumor cells, tumor-associated macrophages and dendritic cells, as well as by effector T cells (Teff) in the setting of an inflammatory anti-tumor response. Preclinical studies with orally-available CCR4 antagonists have demonstrated potent inhibition of Treg migration into tumors, an increase in the intratumoral Teff/Treg ratio, and anti-tumor efficacy as a single agent and in combination with checkpoint inhibitors. In a first-in-human trial conducted in healthy volunteers, the oral CCR4 antagonist FLX475 was demonstrated to be well tolerated with outstanding PK properties. A robust PD assay measuring receptor occupancy on circulating Treg demonstrated the ability to safely achieve exposure levels predicted to maximally inhibit Treg recruitment into tumors via CCR4 signaling. These human PK, PD, and safety data have enabled a streamlined design of a Phase 1/2 study of FLX475 in cancer patients both as monotherapy and in combination with checkpoint inhibitor. Methods: This clinical trial is a Phase 1/2, open-label, dose-escalation and cohort expansion study to determine the safety and preliminary anti-tumor activity of FLX475 as monotherapy and in combination with pembrolizumab. The study is being conducted in 2 parts, a dose-escalation phase (Part 1) and a cohort expansion phase (Part 2). In Part 1 (Phase 1) of the study, at least 3 to 6 eligible subjects will be enrolled in sequential cohorts treated with successively higher doses of FLX475 as monotherapy or in combination with pembrolizumab (Part 1b). In Part 2 (Phase 2) of the study, expansion cohorts of both checkpoint-naïve and checkpoint-experienced patients with tumor types predicted to be enriched for Treg and/or CCR4 ligand expression (i.e. “charged tumors”) -- including both EBV+ and HPV+ tumors and NSCLC, HNSCC, and TNBC -- will be enrolled using a Simon 2-stage design. As of November 6, 2018, Cohort 1 has been completed without DLT. Clinical trial information: NCT03674567.

A phase I, first-in-human, open label, dose-escalation and cohort expansion study of MGD019, a bispecific DART protein binding PD-1 and CTLA-4 in patients with unresectable or metastatic neoplasms.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS2661-TPS2661
Author(s):  
Jason J. Luke ◽  
Manish Sharma ◽  
Rachel E. Sanborn ◽  
Gregory Michael Cote ◽  
Johanna C. Bendell ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Dose Escalation ◽  
Cell Function ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Single Agent ◽  
Open Label ◽  
Biopsy Specimens

TPS2661 Background: Immune checkpoint molecules, including CTLA-4 and PD-1, attenuate the duration and strength of adaptive immune responses to limit immune-mediated tissue damage. Tumors may inhibit cellular immune activation by expressing ligands that bind checkpoint molecules and inhibit T-cell function in the tumor microenvironment. Blockade of these inhibitory pathways is the primary mechanism of action of several novel cancer immunotherapy agents. Combined blockade of PD-1 and CTLA-4 with two checkpoint inhibitors, ipilimumab and nivolumab, increases antitumor activity beyond either single agent alone in patients with metastatic melanoma or other malignancies. MGD019, a novel bispecific molecule that co-engages and coordinately inhibits both PD-1 and CTLA-4 signaling, was developed to potentially improve antitumor activity and/or safety relative to the monoclonal antibody combination. MGD019 is an Fc-bearing tetravalent DART molecule (bivalent for each antigen) that can independently block either checkpoint molecule, with preferential co-blockade in cells co-expressing both molecules demonstrated in vitro. It is hypothesized that MGD019 might be clinically active in either checkpoint naïve or checkpoint experienced patients after prior PD-1/PD-L1 inhibitors. Methods: This Phase 1 study will characterize safety, dose limiting toxicities, and maximum tolerated dose (MTD)/maximum administered dose (MAD) of MGD019. Dose Escalation will enroll patients with advanced solid tumors of any histology in sequential escalating doses in cohorts of 3 to 9 patients in a 3+3+3 design. Once the MTD/MAD is reached, a Cohort Expansion phase will characterize safety and initial antitumor activity per RECIST v1.1 and irRECIST in patients with specific tumor types anticipated to be sensitive to dual checkpoint blockade. Additional endpoints include pharmacokinetics; immunogenicity; impact of MGD019 on various measures of immune-regulatory effects in peripheral blood and biopsy specimens; and relationship between antitumor activity and gene profiles, tumor mutational burden, and PD-1, PD-L1, and CTLA-4 expression on tumor cells and immune cell infiltrates within biopsy specimens. Patients will be followed for survival approximately every 3 months for 2 years. Clinical trial information: NCT03761017.

Phase I study of NBTXR3 activated by radiotherapy in patients with advanced cancers treated with an anti-PD-1 therapy.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS3173-TPS3173 ◽  
Author(s):  
Colette Shen ◽  
Jessica Frakes ◽  
Jared Weiss ◽  
Jimmy J. Caudell ◽  
Trevor G Hackman ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Lung Metastases ◽  
Objective Response ◽  
Intratumoral Injection ◽  
Primary Objective ◽  
Open Label ◽  
Open Label Phase

TPS3173 Background: Despite the past decade of transformative advances in immuno-oncology, the response rate to checkpoint inhibitors (ICIs) remains low (~15%). There is significant interest in developing strategies to overcome resistance to these treatments, thus increasing response rate. Emerging evidence suggests that radiation therapy (RT) could potentially augment the antitumor response to ICIs through synergic effect. However, RT dose and ultimate efficacy are limited by toxicity related to exposure of healthy tissues. NBTXR3 is a first-in-class radioenhancer administered by direct intratumoral injection, designed at the nanoscale to increase RT dose deposition within tumor cells and RT-dependent tumor cell killing, without increasing surrounding normal tissue toxicity. Preclinical and early clinical data suggest NBTXR3 activated by RT can trigger an anti-tumor immune response, producing both local and systemic (abscopal) effects. We hypothesize that NBTXR3 activated by RT, in combination with anti-PD-1 therapy (R3/RT/PD-1), will act synergistically to maximize the local RT effect and produce a systemic response sufficient to increase the proportion of ICI responders or convert ICI non-responders to responders. Methods: This trial [NCT03589339] is a multicenter, open-label, phase I study to evaluate safety and tolerability of R3/RT/PD-1 in three cohorts: (1) Locoregional recurrent or recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) amenable to re-irradiation of the HN field, (2) Lung metastases, or (3) Liver metastases, both from any primary cancer eligible for anti-PD-1 treatment. Approximately two-thirds of patients in each cohort will be anti-PD-1 non-responders. NBTXR3 injected volume is based on a percentage of gross tumor volume (GTV). The primary objective is to determine the R3/RT/PD-1 recommended phase 2 dose in each cohort. Secondary objectives are to evaluate anti-tumor response (objective response rate; ORR), safety and feasibility of NBTXR3 injection, and NBTXR3 body kinetic profile. Exploratory objectives will assess biomarkers of R3/RT/PD-1 response, including PD-L1 status by IHC, as well as mRNA and cytokine immune marker profiling. To date, three patients have been treated, one in cohort 1, two in cohort 2. Clinical trial information: NCT03589339 .

Phase I/II dose-escalation and expansion study of FLX475 alone and in combination with pembrolizumab in advanced cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS3163-TPS3163
Author(s):  
John D. Powderly ◽  
Bartosz Chmielowski ◽  
Julie R. Brahmer ◽  
Sarina Anne Piha-Paul ◽  
Samantha Elizabeth Bowyer ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
Dose Escalation ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Single Agent ◽  
Safety Data ◽  
Receptor Occupancy ◽  
Phase 2 ◽  
Open Label

TPS3163 Background: Regulatory T cells (Treg) can dampen anti-tumor immune responses in the tumor microenvironment (TME). The predominant chemokine receptor on human Treg is CCR4, the receptor for the chemokines CCL17 and CCL22, which are produced by tumor cells, tumor-associated macrophages and dendritic cells, as well as by effector T cells (Teff) in the setting of an inflammatory anti-tumor response. Preclinical studies with orally-available CCR4 antagonists have demonstrated potent inhibition of Treg migration into tumors, an increase in the intratumoral Teff/Treg ratio, and anti-tumor efficacy as a single agent and in combination with checkpoint inhibitors. In a first-in-human trial conducted in healthy volunteers, the oral CCR4 antagonist FLX475 was demonstrated to be well tolerated with outstanding PK properties. A robust PD assay measuring receptor occupancy on circulating Treg demonstrated the ability to safely achieve exposure levels predicted to maximally inhibit Treg recruitment into tumors via CCR4 signaling. These human PK, PD, and safety data have enabled a streamlined design of a Phase 1/2 study of FLX475 in cancer patients both as monotherapy and in combination with checkpoint inhibitor. Methods: This clinical trial is a Phase 1/2, open-label, dose-escalation and cohort expansion study to determine the safety and preliminary anti-tumor activity of FLX475 as monotherapy and in combination with pembrolizumab. The study is being conducted in 2 parts, a dose-escalation phase (Part 1) and a cohort expansion phase (Part 2). In Part 1 (Phase 1) of the study, at least 3 to 6 eligible subjects are being enrolled in sequential cohorts treated with successively higher doses of FLX475 as monotherapy (Part 1a) or in combination with pembrolizumab (Part 1b). In Part 2 (Phase 2) of the study, expansion cohorts of both checkpoint-naïve and checkpoint-experienced patients with tumor types predicted to be enriched for Treg and/or CCR4 ligand expression (i.e. “charged tumors”) -- including both EBV+ and HPV+ tumors and NSCLC, HNSCC, and TNBC -- will be enrolled using a Simon 2-stage design. As of February 4, 2020, Phase 1 dose escalation has been completed and a recommended Phase 2 dose chosen for both FLX475 monotherapy and combination therapy with pembrolizumab. Enrollment into Phase 2 expansion cohorts has been initiated. Clinical trial information: NCT03674567 .

A phase I dose-escalation and expansion study of JPI-547, a dual inhibitor of PARP/tankyrase in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3113-3113
Author(s):  
Seock-Ah Im ◽  
SeungHwan Lee ◽  
Keun Wook Lee ◽  
Youngjoo Lee ◽  
Joohyuk Sohn ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Checkpoint Inhibitors ◽  
Dose Range ◽  
Single Agent ◽  
Pharmacokinetic Data ◽  
Advanced Solid Tumors ◽  
Dual Inhibitor ◽  
Expansion Phase

3113 Background: JPI-547 is an oral inhibitor of PARP 1/2 and Tankyrase 1/2. JPI-547 demonstrated anti-tumor activity in BRCA-deficient xenograft models as a single-agent and in combination with chemotherapy and immune checkpoint inhibitors. Methods: This is the first in human (FIH) phase I study of JPI-547 in patients (pts) with advanced solid tumors. For the dose escalation phase, a 3+3 design was used with 4 doses from 50 to 200 mg QD on 21-day cycles. Primary objectives were to assess safety and tolerability to determine RP2D, and secondary objectives included pharmacokinetics and preliminary antitumor activities. DLT monitoring period was 21 days. Pharmacodynamics and information of HRR mutation were also explored. For the dose expansion phase, pts with documented pathogenic germline or somatic BRCA/HRR mutations were enrolled to assess the preliminary efficacy and safety. Tumor response (RECIST 1.1) was evaluated every 6 weeks. Centralized germline BRCA testing was conducted to confirm pathogenic gBRCA mutations. Results available at the cut-off date of 31-Dec-2020 are presented. Results: For dose escalation phase, 22 pts were enrolled. JPI-547 was well absorbed with Tmax of 0.25-8 h post-dose and apparent half-life of 18-31 h. Mean Cmax and AUC increased proportionally (within the dose range of 50-200 mg). PAR level measured from PBMC was 53% inhibited at Cmax. One DLTs was observed at 100 mg (elevated ALT, G3) and 200 mg (elevated ALT/AST, G3) respectively. MTD was determined as 200 mg after considering DLTs and myelosuppression observed from cycle 2. RP2D was determined to be 150 mg based on the pharmacokinetic data and safety. Thirteen pts (59.1%) had at least one grade 3/4 TRAE and 12 had dose interruption/reduction due to TRAE. The most common ( > 20%) TRAE were anemia, thrombocytopenia and neutropenia. In dose expansion phase, 40 pts were enrolled, and response was evaluable in 39 pts. The best overall responses were 11 confirmed PR (cPR) and 15 SD with ORR of 28.2% (11/39) and DCR of 64.1 % (25/39). The mPFS was 3.5 mos and mDoR was 3.4 mos. At the time of data cut-off, three pts were ongoing as following response and cancer types: cPR (breast, ATMm, 9.0 mos), cPR (NSCLC, gBRCA2m, 3.8 mos) and SD (breast, gBRCAm, 9.3 mos). Five pts (2 ovarian, 3 breast) previously treated with olaparib and discontinued due to progressive disease were enrolled in this JPI-547 trial and one ovarian cancer pt showed cPR with 37% tumor shrinkage. Conclusions: These results demonstrate that JPI-547 is adequately absorbed with acceptable safety profile. Preliminary efficacy results suggest that JPI-547 monotherapy is effective in pts with BRCA/HRR mutation. Further investigation is warranted in pts with solid tumor including PARP inhibitor resistant cases. Clinical trial information: NCT04335604.

A phase I study of AK119, an anti-CD73 monoclonal antibody, in combination with AK104, an anti-PD-1/CTLA-4 bispecific antibody, in patients with advanced or metastatic solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS2675-TPS2675
Author(s):  
Ben Markman ◽  
Amy Hsin-Chieh Hsieh ◽  
Jermaine Coward ◽  
Matteo S. Carlino ◽  
Sophia Frentzas ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Bispecific Antibody ◽  
Checkpoint Inhibitors ◽  
Primary Objective ◽  
Open Label ◽  
Tumor Types ◽  
Anti Tumor Activity

TPS2675 Background: AK119 is a humanized IgG1 monoclonal antibody (mAb) that selectively binds to and inhibits the ectonucleotidase activity of CD73, a cell surface enzyme that converts adenosine monophosphate (AMP) into adenosine. Adenosine has been shown to facilitate tumor-mediated evasion. CD73 inhibition may therefore reduce adenosine accumulation and promote anti-tumor immunity. AK104 is a recombinant humanized IgG1 bispecific antibody that simultaneously binds to programmed cell death protein 1 (PD-1) and cytotoxic T- lymphocyte-associated antigen protein 4 (CTLA-4). Preliminary data from phase I and II studies suggest that AK104 has encouraging anti-tumor activity in selected tumor types and an improved safety profile compared to the co-administration of anti-PD-1 plus anti-CTLA-4 mAbs. Preclinical studies show that CD73 inhibition synergistically increases the anti-tumor activity of PD-1 and CTLA-4 immune checkpoint inhibitors (ICIs). Published early clinical data suggests that anti-CD73 therapy in combination with ICIs produces improved clinical outcomes. Thus, AK119 plus AK104 is postulated to have synergistically enhanced anti-tumor activity compared to the administration of anti-CD73 monotherapy or ICIs alone. Methods: This is a phase 1a/1b, first-in-human, multicenter, open-label study in patients with advanced solid tumors that are refractory to standard therapies. The primary objective is to assess safety, tolerability and dose limiting toxicity; and to determine the Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) of AK119 in combination with AK104. Secondary objectives are to evaluate antitumor activity, PK and AK119 immunogenicity. The dose-escalation phase will evaluate 5 dose levels of AK119 (1mg/kg to 40 mg/kg Q2W IV) in combination with 6mg/kg AK104 Q2W IV using a 3+3+3 study design. Eligible pts will receive a single dose of AK119 on C0D1 of a 14-day “lead-in” period. Thereafter, from C1D1 pts will receive AK119 in combination with AK104 on a 28-day cycle, until unacceptable toxicity, confirmed progressive disease, subject withdrawal, or for a maximum of 24 months. The “lead-in” period is only applicable for dose-escalation cohorts. Any dose-escalation cohort not exceeding the MTD may be expanded to a maximum of 18 subjects with selected solid tumor types for further evaluation of safety, PK/ PD, immunogenicity, and preliminary anti-tumor activity. Cohort 1 is currently in progress with the first patient enrolled in January 2021. For the dose-expansion phase, cohorts of pts with advanced/metastatic pancreatic cancer or MSS/pMMR colorectal cancer will be enrolled. Cohorts of other tumor types may be added based on emerging pharmacodynamic and anti-tumor response data. Clinical trial information: NCT04572152.

Activity of Combined Flavopiridol and Lenalidomide in Patients with Cytogenetically High Risk Chronic Lymphocytic Leukemia (CLL): Updated Results of a Phase I Trial,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3910-3910
Author(s):  
Kristie A. Blum ◽  
Lai Wei ◽  
Jeffrey A. Jones ◽  
Leslie A Andritsos ◽  
Joseph M. Flynn ◽  
...  
Keyword(s):  
High Risk ◽  
Combination Therapy ◽  
Phase I ◽  
Dose Escalation ◽  
Phase I Trial ◽  
Single Agent ◽  
Significant Activity ◽  
Upper Respiratory Tract ◽  
Off Label ◽  
Grade 3

Abstract Abstract 3910 Background: The cyclin dependent kinase inhibitor, flavopiridol, and the immunomodulatory agent, lenalidomide, are active in heavily pre-treated CLL patients (pts) with bulky adenopathy and adverse cytogenetics, although dose escalation of these two agents has been limited by tumor lysis syndrome (TLS) and tumor flare. Furthermore, these agents do not deplete T-cells, and combination therapy may result in greater efficacy and less infectious toxicity than observed with fludarabine or alemtuzumab combinations. Methods: We conducted a phase I trial of combined flavopiridol and lenalidomide in pts with CLL relapsed after at least 1 prior therapy, WBC < 150,000/mm3, ANC > 1000/mm3, platelets > 30,000/mm3, and creatinine < 1.5 mg/dL. Treatment consisted of flavopiridol alone, 30 mg/m2 bolus + 30–50 mg/m2 4-hour continuous IV infusion (CIVI) days 1, 8, and 15 of cycle 1. Starting in cycle 2, flavopiridol 30 mg/m2 bolus + 30–50 mg/m2 4-hour CIVI days 3, 10, and 17 was combined with lenalidomide 2.5, 5.0, 7.5, 10, 15, or 25 mg days 1–21 every 35 days. All pts received 20 and 4 mg of dexamethasone 30 minutes prior to and 24 hours after flavopiridol, respectively, to minimize cytokine release symptoms. Pegfilgrastim was administered on day 18 of cycles 2–8. Results : Thirty pts (18 males) with a median age of 60 (range 42–74) previously treated with a median of 3 prior therapies (range 1–10) were enrolled. All pts received prior fludarabine and 40% were fludarabine refractory. Seventy-three percent of patients were Rai stages III-IV, 60% pts had bulky adenopathy > 5 cm, 60% pts had del(17p13.1), 37% pts had del(11q22.3), and 83% pts had a complex karotype. Twenty-five pts completed two or more cycles of therapy (median 3.5, range 1–8). Five pts completed only one cycle of therapy and were removed prior to receiving lenalidomide due to progressive disease (n=2), TLS requiring dialysis (n=2), and grade 4 thrombocytopenia (n=1). Pts received 2.5 mg (n=6), 5.0 mg (n=7), 7.5 mg (n=4), and 10 mg (n=3) of lenalidomide with 30 mg/m2 bolus + 30 mg/m2 4-hour CIVI flavopiridol and 5 patients have received 10 mg of lenalidomide with 30 mg/m2 bolus + 50 mg/m2 4-hour CIVI flavopiridol. DLT consisting of grade 3–4 transaminitis persisting > 7 days occurred in 2 pts treated with 2.5 mg (n=1) and 5.0 mg of lenalidomide (n=1), respectively. Grade 3–4 toxicities consisted of thrombocytopenia (60%), diarrhea (57%), transient transaminitis (47%), neutropenia (47%), hyperglycemia (47%), infection (43%, pneumonia in 5 pts, upper respiratory tract infection in 2 pts, cellulitis in 1 pt, herpes simplex stomatitis in 1 pt, oral candidiasis in 1 pt, catheter-associated in 1 pt, and febrile neutropenia without a source in 2 pts), hypokalemia (37%), anemia (33%), hypophosphatemia (33%), hypocalcemia (17%), hyperkalemia (17%), TLS requiring dialysis (7%), tumor flare (3%), and rash (3%). In 23 evaluable pts who completed 1 or more cycles of combined lenalidomide and flavopiridol, partial responses were observed in 13 pts (57%), including 7 pts with del(17p13.1), 6 pts with del(11q22.3), 9 pts with complex cytogenetics, 5 fludarabine-refractory pts, and 6 pts with bulky lymphadenopathy. Six pts were able to proceed to allogeneic transplant after 1–3 cycles, and 4 of these pts remain in remission. Median PFS and OS are 7 months (range 0–24 months; 95% CI 5, 11) and 23 months (range 0–27 months; 95% CI 13, 27), respectively. No significant differences have been observed in the single agent and combination PK parameters (AUC, Cmax, T ½, and Clearance) of lenalidomide and flavopiridol. Conclusions: Combined flavopiridol and lenalidomide is well tolerated without increased risks of TLS or tumor flare, with significant activity in pts with bulky, cytogenetically high-risk CLL. This combination regimen could be utilized to de-bulk high risk pts prior to stem cell transplantation or prior to other oral therapies. The MTD has not been reached and dose escalation continues at a lenalidomide dose that exceeds the single agent MTD in CLL of 5 mg (Maddocks et al, Blood 114: abstract 3445, 2009). Future evaluation of continued maintenance lenalidomide after initial combination therapy is planned. This trial is supported by NCI 1R21 CA133875, NCI P50-CA140158, NCI K23 CA109004, NCI U01 CA076576, LLS SCOR 7080–06, and the D. Warren Brown Foundation. Disclosures: Off Label Use: Flavopiridol and lenalidomide are off-label for the treatment of CLL.

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