ABSTRACT
BACKGROUND: Hereditary angioedema is a rare genetic disease that leads to severe and unpredictable swelling attacks. NTLA-2002 is an in vivo gene-editing therapy based on clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9. NTLA-2002 targets the gene encoding kallikrein B1 (KLKB1), with the goal of lifelong control of angioedema attacks after a single dose. METHODS: In this phase 1 dose-escalation portion of a combined phase 1-2 trial of NTLA-2002 in adults with hereditary angioedema, we administered NTLA-2002 at a single dose of 25 mg, 50 mg, or 75 mg. The primary end points were the safety and side-effect profile of NTLA-2002 therapy. Secondary and exploratory end points included pharmacokinetics, pharmacodynamics, and clinical efficacy determined on the basis of investigator-confirmed angioedema attacks. RESULTS: Three patients received 25 mg of NTLA-2002, four received 50 mg, and three received 75 mg. At all dose levels, the most common adverse events were infusion-related reactions and fatigue. No dose-limiting toxic effects, serious adverse events, grade 3 or higher adverse events, or clinically important laboratory findings were observed after the administration of NTLA-2002. Dose-dependent reductions in the total plasma kallikrein protein level were observed between baseline and the latest assessment, with a mean percentage change of -67% in the 25-mg group, -84% in the 50-mg group, and -95% in the 75-mg group. The mean percentage change in the number of angioedema attacks per month between baseline and weeks 1 through 16 (primary observation period) was -91% in the 25-mg group, -97% in the 50-mg group, and -80% in the 75-mg group. Among all the patients, the mean percentage change in the number of angioedema attacks per month from baseline through the latest assessment was -95%. CONCLUSIONS: In this small study, a single dose of NTLA-2002 led to robust, dose-dependent, and durable reductions in total plasma kallikrein levels, and no severe adverse events were observed. In exploratory analyses, reductions in the number of angioedema attacks per month were observed at all dose levels. (Funded by Intellia Therapeutics; ClinicalTrials.gov number, NCT05120830.).
Subject(s)
Angioedemas, Hereditary , CRISPR-Cas Systems , Gene Editing , Adult , Humans , Angioedema , Angioedemas, Hereditary/blood , Angioedemas, Hereditary/drug therapy , Angioedemas, Hereditary/genetics , Complement C1 Inhibitor Protein/therapeutic use , Dose-Response Relationship, Drug , Gene Editing/methods , Plasma Kallikrein/genetics , Treatment OutcomeABSTRACT
BACKGROUND: Transthyretin amyloidosis, also called ATTR amyloidosis, is a life-threatening disease characterized by progressive accumulation of misfolded transthyretin (TTR) protein in tissues, predominantly the nerves and heart. NTLA-2001 is an in vivo gene-editing therapeutic agent that is designed to treat ATTR amyloidosis by reducing the concentration of TTR in serum. It is based on the clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease (CRISPR-Cas9) system and comprises a lipid nanoparticle encapsulating messenger RNA for Cas9 protein and a single guide RNA targeting TTR. METHODS: After conducting preclinical in vitro and in vivo studies, we evaluated the safety and pharmacodynamic effects of single escalating doses of NTLA-2001 in six patients with hereditary ATTR amyloidosis with polyneuropathy, three in each of the two initial dose groups (0.1 mg per kilogram and 0.3 mg per kilogram), within an ongoing phase 1 clinical study. RESULTS: Preclinical studies showed durable knockout of TTR after a single dose. Serial assessments of safety during the first 28 days after infusion in patients revealed few adverse events, and those that did occur were mild in grade. Dose-dependent pharmacodynamic effects were observed. At day 28, the mean reduction from baseline in serum TTR protein concentration was 52% (range, 47 to 56) in the group that received a dose of 0.1 mg per kilogram and was 87% (range, 80 to 96) in the group that received a dose of 0.3 mg per kilogram. CONCLUSIONS: In a small group of patients with hereditary ATTR amyloidosis with polyneuropathy, administration of NTLA-2001 was associated with only mild adverse events and led to decreases in serum TTR protein concentrations through targeted knockout of TTR. (Funded by Intellia Therapeutics and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT04601051.).
Subject(s)
Amyloid Neuropathies, Familial/genetics , Amyloid Neuropathies, Familial/therapy , CRISPR-Cas Systems , Gene Editing , Liposomes/therapeutic use , Nanoparticles/therapeutic use , Prealbumin/genetics , RNA, Guide, Kinetoplastida/therapeutic use , Female , Gene Transfer Techniques , Humans , Infusions, Intravenous , Male , Middle Aged , Prealbumin/analysis , RNA, MessengerABSTRACT
BACKGROUND: Although several randomised trials in patients with triple-negative breast cancer have shown that the addition of carboplatin, with or without poly(ADP-ribose) polymerase (PARP) inhibitors, to neoadjuvant chemotherapy increases the likelihood of achieving a pathological complete response, the use of these therapies in this setting has remained controversial. The BrighTNess trial was designed to assess the addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer. METHODS: We did a phase 3, randomised, double-blind, placebo-controlled trial (BrighTNess) across 145 sites in 15 countries. Patients aged 18 years and older with previously untreated histologically or cytologically confirmed clinical stage II-III triple-negative breast cancer, who were candidates for potentially curative surgery and had an Eastern Cooperative Oncology Group performance status of 0 or 1, were randomly assigned (2:1:1) by an interactive response technology system via permuted blocks (block size of four) within strata to receive one of three segment 1 regimens: paclitaxel (80 mg/m2 intravenously weekly for 12 doses) plus carboplatin (area under the curve 6 mg/mL per min, intravenously every 3 weeks, for four cycles) plus veliparib (50 mg orally, twice a day); paclitaxel plus carboplatin plus veliparib placebo (twice a day); or paclitaxel plus carboplatin placebo (every 3 weeks for four cycles) plus veliparib placebo. Following segment 1, all patients were assigned to segment 2 in which they received doxorubicin and cyclophosphamide every 2-3 weeks for four cycles. Randomisation for segment 1 was stratified by germline BRCA mutation status, nodal stage, and planned schedule of doxorubicin and cyclophosphamide administration. The primary endpoint was pathological complete response in breast and lymph nodes as determined by site pathologists following completion of neoadjuvant therapy. Efficacy analyses were done by intention to treat and safety analyses included all patients who received at least one dose of study treatment. These are the first results of an ongoing clinical trial; the data cutoff for the analyses presented was Dec 8, 2016. This study is registered with ClinicalTrials.gov, number NCT02032277. FINDINGS: Between April 4, 2014, and March 18, 2016, 634 patients were randomly assigned: 316 to paclitaxel plus carboplatin plus veliparib, 160 to paclitaxel plus carboplatin, and 158 to paclitaxel alone. The proportion of patients who achieved a pathological complete response was higher in the paclitaxel, carboplatin, and veliparib group than in patients receiving paclitaxel alone (168 [53%] of 316 patients vs 49 [31%] of 158, p<0·0001), but not compared with patients receiving paclitaxel plus carboplatin (92 [58%] of 160 patients, p=0·36). Grade 3 or 4 toxicities, and serious adverse events were more common in patients receiving carboplatin, whereas veliparib did not substantially increase toxicity. The most common grade 3 or 4 events overall were neutropenia (352 [56%] of 628 patients), anaemia (180 [29%]), and thrombocytopenia (75 [12%]) through complete treatment, and febrile neutropenia (88 [15%] of 601 patients) during segment 2. The most common serious adverse events were febrile neutropenia (80 [13%] of 628 patients) and anaemia (20 [3%]). INTERPRETATION: Although the addition of veliparib and carboplatin to paclitaxel followed by doxorubicin and cyclophosphamide improved the proportion of patients with triple-negative breast cancer who achieved a pathological complete response, the addition of veliparib to carboplatin and paclitaxel did not. Increased toxicities with the addition of carboplatin (with or without veliparib) to paclitaxel were manageable and did not substantially affect treatment delivery of paclitaxel followed by doxorubicin and cyclophosphamide. Given the consistent results with previous studies, the addition of carboplatin appears to have a favourable risk to benefit profile and might be considered as a potential component of neoadjuvant chemotherapy for patients with high-risk, triple-negative breast cancer. FUNDING: AbbVie.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Triple Negative Breast Neoplasms/drug therapy , Adult , Anemia/chemically induced , Benzimidazoles/administration & dosage , Benzimidazoles/adverse effects , Carboplatin/administration & dosage , Carboplatin/adverse effects , Chemotherapy, Adjuvant , Chemotherapy-Induced Febrile Neutropenia/etiology , Cyclophosphamide/administration & dosage , Disease-Free Survival , Double-Blind Method , Doxorubicin/administration & dosage , Female , Genes, BRCA1 , Genes, BRCA2 , Humans , Lymph Node Excision , Lymph Nodes/pathology , Lymphatic Metastasis , Mastectomy , Middle Aged , Mutation , Neoadjuvant Therapy , Paclitaxel/administration & dosage , Survival Rate , Thrombocytopenia/chemically induced , Treatment Outcome , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/pathology , Triple Negative Breast Neoplasms/surgery , Tumor Burden/drug effectsABSTRACT
OBJECTIVE: Determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of veliparib combined with carboplatin and gemcitabine in patients with advanced ovarian cancer and other nonhematologic malignancies. METHODS: In this phase I study, patients with metastatic or unresectable solid tumors and ≤2 prior chemotherapy regimens received veliparib combined with carboplatin area under the curve (AUC) 4 on day 1 and gemcitabine 800mg/m2 on days 1 and 8 of a 21-day cycle for maximum 10cycles, followed by optional veliparib maintenance therapy. Veliparib dosing commenced twice-daily (BID) continuously on day 1 of cycle 2; granulocyte colony-stimulating factor was permitted. Dose escalation used a Bayesian continual reassessment method. Safety, tolerability, and efficacy were evaluated. RESULTS: Seventy-five patients were enrolled (ovarian cancer, n=54; breast cancer, n=12). Thirty-six patients with ovarian cancer (67%) had known germline BRCA mutations. Most common treatment-related adverse events (TRAEs; ≥60%) were thrombocytopenia, neutropenia, nausea, and anemia. Most common grade 3/4 TRAEs (≥40%) were neutropenia and thrombocytopenia. Dose-limiting toxicities were thrombocytopenia and neutropenia. The MTD/RP2D was established at veliparib 250mg with carboplatin AUC 4 plus gemcitabine 800mg/m2. Responses were observed in 69% of patients with BRCA-deficient ovarian cancer (45% partial, 24% complete responses). Five patients remained on veliparib (80-310mg BID) for >34cycles. CONCLUSIONS: Veliparib plus carboplatin/gemcitabine is tolerated, with a safety profile similar to carboplatin and gemcitabine alone. Combination therapy demonstrated promising preliminary antitumor activity in platinum-sensitive ovarian cancer patients with germline BRCA mutations. Trial registration ID: NCT01063816.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Ovarian Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Anemia/chemically induced , Area Under Curve , Bayes Theorem , Benzimidazoles/administration & dosage , Bile Duct Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Carboplatin/administration & dosage , Carcinoma, Basal Cell/drug therapy , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Transitional Cell/drug therapy , Cholangiocarcinoma/drug therapy , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Female , Gallbladder Neoplasms/drug therapy , Genes, BRCA1 , Genes, BRCA2 , Germ-Line Mutation , Humans , Induction Chemotherapy , Kidney Neoplasms/drug therapy , Kidney Pelvis , Liver Neoplasms/drug therapy , Lung Neoplasms/drug therapy , Maintenance Chemotherapy , Male , Maximum Tolerated Dose , Mesothelioma/drug therapy , Middle Aged , Nausea/chemically induced , Neoplasm Metastasis , Neutropenia/chemically induced , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , Poly(ADP-ribose) Polymerase Inhibitors/administration & dosage , Prostatic Neoplasms/drug therapy , Skin Neoplasms/drug therapy , Thrombocytopenia/chemically induced , Treatment Outcome , GemcitabineABSTRACT
BACKGROUND: Ilorasertib (ABT-348) is a novel inhibitor of Aurora kinase, vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptors, and the Src families of tyrosine kinases. Ilorasertib alone or in combination with azacitidine demonstrated activity in preclinical models in various hematological malignancies, indicating that pan-Aurora kinase and multiple kinase inhibition may have preferential antileukemic activity. This phase 1 trial determined the safety, pharmacokinetics, and preliminary antitumor activity of ilorasertib alone or combined with azacitidine in advanced hematologic malignancies. PATIENTS AND METHODS: Fifty-two patients (median age, 67 years; 35 % with >4 prior regimens) with acute myelogenous leukaemia (AML; n = 38), myelodysplastic syndrome (n = 12), or chronic myelomonocytic leukaemia (n = 2) received 3 or 6 doses of ilorasertib per 28-day cycle and were assigned to arm A (once-weekly oral), B (twice-weekly oral), C (once-weekly oral plus azacitidine), or D (once-weekly intravenous) treatment. RESULTS: Maximum tolerated doses were not determined; the recommended phase 2 oral monotherapy doses were 540 mg once weekly and 480 mg twice weekly. The most common grade 3/4 adverse events were hypertension (28.8 %), hypokalemia (15.4 %), anemia (13.5 %), and hypophosphatemia (11.5 %). Oral ilorasertib pharmacokinetics appeared dose proportional, with a 15-hour half-life and no interaction with azacitidine. Ilorasertib inhibited biomarkers for Aurora kinase and VEGF receptors, and demonstrated clinical responses in 3 AML patients. CONCLUSIONS: Ilorasertib exhibited acceptable safety and pharmacokinetics at or below the recommended phase 2 dose, displayed evidence of dual Aurora kinase and VEGF receptor kinase inhibition, and activity in AML.
Subject(s)
Aminopyridines , Antineoplastic Agents , Hematologic Neoplasms/drug therapy , Phenylurea Compounds , Protein Kinase Inhibitors , Aged , Aminopyridines/adverse effects , Aminopyridines/pharmacokinetics , Aminopyridines/therapeutic use , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols , Aurora Kinases/antagonists & inhibitors , Azacitidine/adverse effects , Azacitidine/pharmacokinetics , Azacitidine/therapeutic use , Female , Hematologic Neoplasms/metabolism , Humans , Male , Maximum Tolerated Dose , Phenylurea Compounds/adverse effects , Phenylurea Compounds/pharmacokinetics , Phenylurea Compounds/therapeutic use , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Receptors, Vascular Endothelial Growth FactorABSTRACT
The antibody HMB45 is used to diagnose lymphangioleiomyomatosis, a hyperproliferative disorder of lung smooth muscle cells with mutations in both alleles of either TSC1 or TSC2. A subset of these tumor cells expresses the melanoma-associated antigens gp100 and melanoma antigen recognized by T cells (MART-1). To explore the feasibility of targeting tumors in lymphangioleiomyomatosis by melanoma immunotherapy, we therefore assessed melanoma target antigen expression and existing immune infiltration of affected tissue compared with normal lung and melanoma as well as the susceptibility of cultured lymphangioleiomyomatosis cells to melanoma reactive cytotoxic T lymphocytes in vitro. Tumors expressed tyrosinase-related proteins 1 and 2 but not tyrosinase, in addition to gp100 and MART-1, and were densely infiltrated by macrophages, but not dendritic cells or T cell subsets. Although CD8(+) lymphocytes were sparse compared with melanoma, cells cultured from lymphangioleiomyomatosis tissue were susceptible to cytotoxic, gp100 reactive, and major histocompatibility complex class I restricted CD8(+) T cells in functional assays. Responder T cells selectively clustered and secreted interferon-gamma in response to HLA-matched melanocytes and cultured lymphangioleiomyomatosis cells. This reactivity exceeded that based on detectable gp100 expression; thus, tumor cells in lymphangioleiomyomatosis may process melanosomal antigens different from melanocytic cells. Therefore, boosting immune responses to gp100 in lymphangioleiomyomatosis may offer a highly desirable treatment option for this condition.
Subject(s)
Antigens, Neoplasm/immunology , Cytotoxicity, Immunologic , Lymphangioleiomyomatosis/immunology , Membrane Glycoproteins/immunology , Neoplasm Proteins/immunology , T-Lymphocytes, Cytotoxic/immunology , Antigens, Neoplasm/metabolism , Cell Separation , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Humans , Immunohistochemistry , Immunotherapy/methods , Intramolecular Oxidoreductases/immunology , Intramolecular Oxidoreductases/metabolism , Lymphangioleiomyomatosis/metabolism , Lymphocytes, Tumor-Infiltrating/immunology , MART-1 Antigen , Melanoma/immunology , Membrane Glycoproteins/metabolism , Microscopy, Electron, Transmission , Neoplasm Proteins/metabolism , Oxidoreductases/immunology , Oxidoreductases/metabolism , Skin Neoplasms/immunology , gp100 Melanoma AntigenABSTRACT
Importance: Neoadjuvant systemic therapy (NST) is often administered to enable breast-conserving therapy (BCT) in stages II to III breast cancer. Objectives: To prospectively evaluate the role of NST in conversion from BCT ineligibility to BCT eligibility and to assess the association of response to NST, germline BRCA (gBRCA) status, and region of treatment with surgical choice in women with triple-negative breast cancer (TNBC). Design, Setting, and Participants: This prespecified secondary analysis of a multicentered, phase 3, double-blind, randomized clinical trial (BrighTNess) enrolled 634 eligible women across 145 centers in 15 countries in North America, Europe, and Asia. Women with operable, clinical stages II to III TNBC who underwent gBRCA mutation testing before initiating NST were eligible to participate. Data were collected from April 1, 2014, to December 8, 2016. This preplanned analysis was performed from January 5, 2018, to October 28, 2019. Interventions: Study participants were randomized to receive 12 weeks of weekly paclitaxel alone or with the addition of carboplatin and/or veliparib, followed by 4 cycles of doxorubicin hydrochloride and cyclophosphamide. Main Outcomes and Measures: Surgeons assessed BCT candidacy by clinical and radiographic criteria before and after NST. Surgical choices and whether BCT eligibility was associated with the likelihood of pathologic complete response were then analyzed. Results: Among the 634 randomized patients (median age, 51 [range, 22-78] years), pre- and post-NST assessments were available for 604 patients. Of 141 patients deemed BCT ineligible at baseline, 75 (53.2%) converted to BCT eligible. Overall, 342 (68.1%) of 502 patients deemed BCT eligible after NST underwent BCT, including 42 (56.0%) of the 75 who converted to BCT eligible. Patients treated in Europe and Asia were more likely to undergo BCT (odds ratio, 2.66; 95% CI, 1.84-3.84) compared with those treated in North America. Among patients without gBRCA mutation undergoing mastectomy, those treated in North America were more likely to undergo contralateral prophylactic mastectomy (57 of 81 [70.4%] vs 6 of 30 [20.0%]; P < .001). Rates of pathologic complete response were similar between patients deemed BCT eligible at baseline and those who were BCT ineligible but converted to BCT eligibility after NST (55.3 [235 of 425] vs 49.3% [37 of 75]; P = .38). Conclusions and Relevance: This prospective analysis of NST and BCT eligibility in TNBC demonstrates a conversion from BCT ineligibility to BCT eligibility of 53.2%. Lower BCT rates among eligible patients and higher bilateral mastectomy rates among patients without gBRCA mutation in North America merit investigation. Trial Registration: ClinicalTrials.gov identifier: NCT02032277.
Subject(s)
Mastectomy, Segmental , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/surgery , Adult , Aged , Chemotherapy, Adjuvant , Double-Blind Method , Female , Humans , Middle Aged , Neoadjuvant Therapy , Patient Selection , Prospective Studies , Treatment Outcome , Young AdultABSTRACT
Targeted cancer chemotherapy agents interfere with receptor tyrosine kinase signaling pathways that promote tumor cell growth. Targeted agents inhibit receptor tyrosine kinase signaling by binding the extracellular component of a growth receptor, binding the soluble ligand that triggers the receptor, or binding intracellular sites that interfere with downstream signaling events. Since their introduction, targeted agents have proved effective for the treatment of locally advanced, metastatic, and micrometastatic solid tumors. In this article, the targeted agents used for solid malignancies and the evidence for current tumor-specific therapies are reviewed.
Subject(s)
Antineoplastic Agents/therapeutic use , Neoplasms/drug therapy , Neoplasms/metabolism , Protein Kinase Inhibitors/therapeutic use , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/metabolism , ErbB Receptors/drug effects , Female , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Male , Neoplasms/enzymology , Neoplasms/pathology , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/metabolism , Signal Transduction/drug effects , Vascular Endothelial Growth Factor A/antagonists & inhibitorsABSTRACT
Adoptive T cell immunotherapy is the isolation of tumor-specific T cells from a cancer patient, in vitro activation and expansion of these T cells, and re-infusion of the T cells to the patient. In a small percentage of patients with tumor types susceptible to immune modulation, adoptive therapy has proven to be highly effective. The use of adoptive therapy has several limitations which are being actively investigated today. T cells from various sources are being isolated for adoptive therapy: lymphocytes can be isolated from tumor lesions, from lymph nodes draining the tumor or a tumor vaccine site, or from peripheral blood lymphocytes stimulated with tumor antigens in vitro. Recent advances in T cell therapy include enhanced efficacy of T cell therapy following non-myeloablative chemotherapy and genetic modification of T cells for use in adoptive therapy. Clinical trials using gene-modified T cells with improved activation, lifespan, and tumor targeting are on the horizon. It is likely that adoptive immunotherapy will remain a fertile area for investigation resulting in advances in the fields of T cell biology and gene therapy. Adoptive therapy for cancer will become widespread only after its clinical benefit for sizeable patient populations has been established.
Subject(s)
Immunotherapy, Adoptive , Neoplasms/therapy , T-Lymphocytes/transplantation , Animals , Combined Modality Therapy , Genetic Engineering , Humans , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/transplantation , Neoplasms/drug therapy , T-Lymphocytes/immunology , TransgenesABSTRACT
BACKGROUND: Omaveloxolone is a semisynthetic oleanane triterpenoid that potently activates Nrf2 with subsequent antioxidant function. We conducted a first-in-human Phase I clinical trial (NCT02029729) with the primary objectives to determine the appropriate dose for Phase II studies, characterize pharmacokinetic and pharmacodynamic parameters, and assess antitumor activity. METHODS: Omaveloxolone was administered orally once daily continuously in a 28-day cycle for patients with stage 4 relapsed/refractory melanoma or non-small cell lung cancer. An accelerated titration design was employed until a grade 2-related adverse event (AE) occurred. A standard 3+3 dose escalation was employed. Single-dose and steady-state plasma pharmacokinetics of the drug were characterized. Downstream Nrf2 activation was assessed in peripheral blood mononuclear cells by quantification of target gene mRNA expression. RESULTS: Omaveloxolone was tested at four dose levels up to 15 mg given orally once daily. No dose-limiting toxicities were detected, and the maximum tolerated dose was not determined. All drug-related AEs were either grade 1 or 2 in severity, and none required clinical action. The most common drug-related AEs were elevated alkaline phosphatase (18%) and anemia (18%). No drug interruptions or reductions were required. Omaveloxolone was rapidly absorbed and exhibited proportional increases in exposure across dose levels. With some exceptions, an overall trend toward time-dependent and dose-dependent activation of Nrf2 antioxidant genes was observed. No confirmed radiologic responses were seen, although one lung cancer subject did have stable disease exceeding 1 year. CONCLUSIONS: Omaveloxolone has favorable tolerability at biologically active doses, although this trial had a small sample size which limits definitive conclusions. These findings support further investigation of omaveloxolone in cancer.
ABSTRACT
In the last two decades, great advances have been made studying the immune response to human tumors. The identification of protein antigens from cancer cells and better techniques for eliciting antigen specific T cell responses in vitro and in vivo have led to improved understanding of tumor recognition by T cells. Yet, much remains to be learned about the intricate details of T cell-tumor cell interactions. Though the strength of interaction between T cell and target is thought to be a key factor influencing the T cell response, investigations of T cell avidity, T cell receptor (TCR) affinity for peptide-MHC complex, and the recognition of peptide on antigen presenting targets or tumor cells reveal complex relationships. Coincident with these investigations, therapeutic strategies have been developed to enhance tumor recognition using antigens with altered peptide structures and T cells modified by the introduction of new antigen binding receptor molecules. The profound effects of these strategies on T cell-tumor interactions and the clinical implications of these effects are of interest to both scientists and clinicians. In recent years, the focus of much of our work has been the avidity and effector characteristics of tumor reactive T cells. Here we review concepts and current results in the field, and the implications of therapeutic strategies using altered antigens and altered effector T cells.
ABSTRACT
Despite the wealth of information that has been acquired regarding the way T cells recognize their targets, we are left with far more questions than answers regarding how to manipulate the immune response to better treat cancer patients. Clearly, most patients have a broad repertoire of T cells capable of recognizing their tumor cells. Despite the presence of these tumor reactive T cells and our ability to increase their frequency though vaccination or adoptive transfer, patients still progress. From the T cell side, defects in T cell signaling may account for much of our failure to achieve significant numbers of objective clinical responses. In spite of these negatives, the horizon does remain bright for T cell based immune therapy of cancer. The periodic objective clinical response tells us that immune therapy can work. Now that we know that cancer patients have the capacity to mount immune responses against their tumors, current and future investigations with agents which alter T cell function combined with vaccination or adoptive T cell transfer may help tip the balance towards effective immune therapies.
Subject(s)
Antigens, Neoplasm/immunology , T-Lymphocytes/immunology , Animals , Humans , Lymphocyte Activation/immunology , Receptors, Antigen, T-Cell/immunologyABSTRACT
PURPOSE: This open-label phase III trial evaluated efficacy and tolerability of linifanib versus sorafenib in patients with advanced hepatocellular carcinoma (HCC) without prior systemic therapy. PATIENTS AND METHODS: Patients were randomly assigned in a 1:1 ratio to linifanib 17.5 mg once daily or sorafenib 400 mg twice daily. Patients were stratified by region (Outside Asia, Japan, and rest of Asia), Eastern Cooperative Oncology Group performance score (ECOG PS; 0 or 1), vascular invasion or extrahepatic spread (yes or no), and hepatitis B virus (HBV) infection (yes or no). The primary end point of the study was overall survival (OS). Secondary end points were time to progression (TTP) and objective response rate (ORR) per RECIST v1.1. RESULTS: We randomly assigned 1,035 patients (median age, 60 years; Asian, 66.6%; ECOG PS 0, 65.2%; HBV, 49.1%; vascular invasion or extrahepatic spread, 70.1%). Median OS was 9.1 months on the linifanib arm (95% CI, 8.1 to 10.2) and 9.8 months on the sorafenib arm (95% CI, 8.3 to 11.0; hazard ratio [HR], 1.046; 95% CI, 0.896 to 1.221). For prespecified stratification subgroups, OS HRs ranged from 0.793 to 1.119 and the 95% CI contained 1.0. Median TTP was 5.4 months on the linifanib arm (95% CI, 4.2 to 5.6) and 4.0 months on the sorafenib arm (95% CI, 2.8 to 4.2; HR, 0.759; 95% CI, 0.643 to 0.895; P = .001). Best response rate was 13.0% on the linifanib arm versus 6.9% on the sorafenib arm. Grade 3/4 adverse events (AEs); serious AEs; and AEs leading to discontinuation, dose interruption, and reduction were more frequent with linifanib (all P < .001). CONCLUSION: Linifanib and sorafenib had similar OS in advanced HCC. Predefined superiority and noninferiority OS boundaries were not met for linifanib and the study failed to meet the primary end point. TTP and ORR favored linifanib; safety results favored sorafenib.
Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Hepatocellular/drug therapy , Indazoles/therapeutic use , Liver Neoplasms/drug therapy , Niacinamide/analogs & derivatives , Phenylurea Compounds/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Carcinoma, Hepatocellular/etiology , Carcinoma, Hepatocellular/pathology , Drug Administration Schedule , Female , Hand-Foot Syndrome/etiology , Humans , Hypertension/chemically induced , Indazoles/administration & dosage , Indazoles/adverse effects , Kaplan-Meier Estimate , Liver Neoplasms/etiology , Liver Neoplasms/pathology , Male , Middle Aged , Niacinamide/administration & dosage , Niacinamide/adverse effects , Niacinamide/therapeutic use , Odds Ratio , Phenylurea Compounds/administration & dosage , Phenylurea Compounds/adverse effects , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Risk Factors , Sorafenib , Treatment OutcomeABSTRACT
OBJECTIVES: Linifanib, a potent and selective inhibitor of the tyrosine kinase activity of vascular endothelial growth factor and platelet-derived growth factor receptors, has clinical activity in advanced non-small cell lung cancer (NSCLC) both as monotherapy in the relapsed setting or with carboplatin and paclitaxel in the first-line setting. Though benefit was observed in unselected patient populations, identification of predictive biomarkers is critical for further development of this novel agent. MATERIALS AND METHODS: Data from 4 randomized studies in relapsed NSCLC with linifanib (n=116) or other treatments (n=125) were examined in an exploratory analysis to identify a biomarker profile predictive of favorable survival. RESULTS: A signature combining the established tumor markers carcinoembryonic antigen (CEA) and cytokeratin 19 fragments (CYFRA 21-1) was predictive of a favorable outcome. This signature was associated with improved survival in patients receiving linifanib monotherapy (hazard ratio [HR]=0.51 vs signature negative; p=0.002), but not in those receiving other anti-cancer treatments (p=0.716). This signature was validated on baseline plasma samples from patients enrolled in a randomized trial of daily linifanib 7.5 mg, linifanib 12.5 mg, or placebo added to first-line carboplatin and paclitaxel chemotherapy for advanced, nonsquamous NSCLC. Only linifanib-treated signature-positive patients had significant improvement in progression-free survival (PFS). Median PFS with placebo was 5.2 months versus 10.2 months (HR=0.49, p=0.049) for those receiving linifanib 7.5mg, and 8.3 months (HR=0.38, p=0.029) for linifanib 12.5 mg. Overall survival for signature-positive patients was 11.3 months with placebo, 12.5 months with linifanib 7.5mg (HR=1.02, p=0.758), and 17.4 months with linifanib 12.5 mg (HR=0.54, p=0.137). CONCLUSION: This baseline plasma biomarker signature is associated with improved outcome in advanced NSCLC patients receiving linifanib. Utility of the biomarker signature in patient selection for linifanib therapy in NSCLC merits evaluation in larger, prospective trials that are powered to detect a survival benefit.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/blood , Carcinoma, Non-Small-Cell Lung/blood , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/blood , Lung Neoplasms/drug therapy , Antigens, Neoplasm/metabolism , Carboplatin/administration & dosage , Carcinoembryonic Antigen/metabolism , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Disease-Free Survival , Female , Humans , Indazoles/administration & dosage , Keratin-19/metabolism , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Middle Aged , Paclitaxel/administration & dosage , Phenylurea Compounds/administration & dosageABSTRACT
PURPOSE: Linifanib, a potent, selective inhibitor of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors, has single-agent activity in non-small-cell lung cancer (NSCLC). We evaluated linifanib with carboplatin and paclitaxel as first-line therapy of advanced nonsquamous NSCLC. PATIENTS AND METHODS: Patients with stage IIIB/IV nonsquamous NSCLC were randomly assigned to 3-week cycles of carboplatin (area under the curve 6) and paclitaxel (200 mg/m(2)) with daily placebo (arm A), linifanib 7.5 mg (arm B), or linifanib 12.5 mg (arm C). The primary end point was progression-free survival (PFS); secondary efficacy end points included overall survival (OS) and objective response rate. RESULTS: One hundred thirty-eight patients were randomly assigned (median age, 61 years; 57% men; 84% smokers). Median PFS times were 5.4 months (95% CI, 4.2 to 5.7 months) in arm A (n = 47), 8.3 months (95% CI, 4.2 to 10.8 months) in arm B (n = 44), and 7.3 months (95% CI, 4.6 to 10.8 months) in arm C (n = 47). Hazard ratios (HRs) for PFS were 0.51 for arm B versus A (P = .022) and 0.64 for arm C versus A (P = .118). Median OS times were 11.3, 11.4, and 13.0 months in arms A, B, and C, respectively. HRs for OS were 1.08 for arm B versus A (P = .779) and 0.88 for arm C versus A (P = .650). Both linifanib doses were associated with increased toxicity, including a higher incidence of adverse events known to be associated with VEGF/PDGF inhibition. Baseline plasma carcinoembryonic antigen/cytokeratin 19 fragments biomarker signature was associated with PFS improvement and a trend toward OS improvement with linifanib 12.5 mg. CONCLUSION: Addition of linifanib to chemotherapy significantly improved PFS (arm B), with a modest trend for survival benefit (arm C) and increased toxicity reflective of known VEGF/PDGF inhibitory effects.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Administration, Oral , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carboplatin/administration & dosage , Carcinoma, Non-Small-Cell Lung/mortality , Disease-Free Survival , Drug Administration Schedule , Female , Humans , Indazoles/administration & dosage , Indazoles/adverse effects , Kaplan-Meier Estimate , Lung Neoplasms/mortality , Male , Middle Aged , Paclitaxel/administration & dosage , Phenylurea Compounds/administration & dosage , Phenylurea Compounds/adverse effects , Receptors, Platelet-Derived Growth Factor/antagonists & inhibitors , Treatment Outcome , Vascular Endothelial Growth Factor A/antagonists & inhibitorsABSTRACT
INTRODUCTION: Linifanib is a potent, orally active, and selective inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptor kinase activities with clinical efficacy in non-small cell lung cancer (NSCLC). This phase 1 dose-escalation study evaluated the pharmacokinetics, safety, and efficacy of linifanib in combination with carboplatin/paclitaxel in Japanese patients with advanced NSCLC. METHODS: Carboplatin (AUC = 6 mg/mL/min) and paclitaxel (200 mg/m²) were administered on day 1 of each 21-day cycle up to a maximum of six cycles. Oral linifanib (7.5 mg) was given to six patients once daily throughout all cycles and escalated to 12.5 mg/day in a second cohort of six patients. RESULTS: Twelve patients received at least one dose of linifanib. The most common adverse events were hematologic and consistent with expected toxicities with carboplatin/paclitaxel. With 12.5 mg linifanib, grade 3/4 neutropenia, leukopenia, and thrombocytopenia occurred in 100, 83, and 83 % of patients, respectively. Dose-limiting grade 4 thrombocytopenia occurred in one patient at each dose level. Linifanib pharmacokinetics was similar to that in non-Japanese patients. At 12.5 mg, linifanib Cmax was 0.32 µg/mL and AUC24 was 4.29 µg h/mL. Linifanib Cmax occurred at 2-3 h with both doses and when given alone or in combination with carboplatin/paclitaxel. Exposure to linifanib appeared to be increased by carboplatin/paclitaxel, and exposure to paclitaxel appeared to be increased by linifanib. Partial responses were observed in nine patients. CONCLUSIONS: Linifanib added to carboplatin/paclitaxel is well tolerated in Japanese patients with advanced/metastatic NSCLC. The recommended dose of linifanib with carboplatin/paclitaxel is 12.5 mg, same as for US patients.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma/drug therapy , Indazoles/administration & dosage , Lung Neoplasms/drug therapy , Lung/drug effects , Phenylurea Compounds/administration & dosage , Protein Kinase Inhibitors/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carboplatin/administration & dosage , Carboplatin/adverse effects , Carboplatin/pharmacokinetics , Carboplatin/therapeutic use , Carcinoma/blood , Carcinoma/pathology , Carcinoma/secondary , Carcinoma, Non-Small-Cell Lung/blood , Carcinoma, Non-Small-Cell Lung/pathology , Chemotherapy-Induced Febrile Neutropenia/physiopathology , Cohort Studies , Dose-Response Relationship, Drug , Female , Humans , Indazoles/adverse effects , Indazoles/pharmacokinetics , Indazoles/therapeutic use , Japan , Leukopenia/chemically induced , Leukopenia/physiopathology , Lung/pathology , Lung Neoplasms/blood , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Paclitaxel/administration & dosage , Paclitaxel/adverse effects , Paclitaxel/pharmacokinetics , Paclitaxel/therapeutic use , Phenylurea Compounds/adverse effects , Phenylurea Compounds/pharmacokinetics , Phenylurea Compounds/therapeutic use , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Receptors, Platelet-Derived Growth Factor/antagonists & inhibitors , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Severity of Illness Index , Thrombocytopenia/chemically induced , Thrombocytopenia/physiopathology , Tumor Burden/drug effectsABSTRACT
BACKGROUND: Although CRC is the third most commonly diagnosed cancer in the United States, second-line CRC treatment is limited. In this trial we examined the efficacy and safety of linifanib, an oral, potent, selective tyrosine kinase inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptor families, with mFOLFOX6, compared with bevacizumab and mFOLFOX6, in previously treated metastatic CRC. PATIENTS AND METHODS: One hundred forty-eight patients with advanced CRC previously treated with fluoropyrimidine or irinotecan received bevacizumab (10 mg/kg, intravenous), low-dose linifanib (7.5 mg), or high-dose linifanib (12.5 mg), with mFOLFOX6. The primary end point was progression-free survival (PFS). Secondary objectives included overall survival (OS), objective response rate (ORR), and safety. RESULTS: No statistically significant differences in PFS occurred between bevacizumab and linifanib doses (low, hazard ratio [HR], 1.453 [95% confidence interval [CI], 0.830-2.539]; high, HR, 1.257 [95% CI, 0.672-2.351]). Median OS values were similar for bevacizumab and high-dose linifanib (bevacizumab, 16.5 months [95% CI, 13.0-not available]; high-dose linifanib, 16.4 months [95% CI, 11.9-21.7]; low-dose linifanib, 12.0 months [95% CI, 10.1-13.0]). ORRs were similar (bevacizumab, 34.7% [95% CI, 21.7-49.6]; low-dose linifanib, 24.0% [95% CI, 13.1-38.2]; high-dose linifanib, 22.4% [95% CI, 11.8-36.6]). Median cycles of 5-fluorouracil were reduced in the linifanib arms, versus the bevacizumab arm. Grade 3/4 adverse event occurrences were more frequent with linifanib. Palmar-plantar erythrodysesthesia, hypothyroidism, and thrombocytopenia were more common with high-dose linifanib than bevacizumab. CONCLUSION: Combining linifanib with mFOLFOX6 as a second-line treatment for metastatic CRC did not improve PFS, radiographic findings, or duration of response versus bevacizumab and mFOLFOX6.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bevacizumab , Disease-Free Survival , Female , Fluorouracil/administration & dosage , Hand-Foot Syndrome/etiology , Humans , Hypothyroidism/chemically induced , Indazoles/administration & dosage , Leucovorin/administration & dosage , Male , Middle Aged , Organoplatinum Compounds/administration & dosage , Phenylurea Compounds/administration & dosage , Survival Rate , Thrombocytopenia/chemically induced , Young AdultABSTRACT
PURPOSE: This phase 1 study assessed the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of linifanib in Japanese patients with advanced solid tumors. METHODS: Patients were assigned to one of four sequential cohorts (0.05, 0.10, 0.20, or 0.25 mg/kg) of oral, once-daily linifanib on a 21-day cycle. Adverse events (AEs) were assessed per common terminology criteria for adverse events v3.0; tumor responses were assessed by response evaluation criteria in solid tumors. RESULTS: Eighteen patients were enrolled. Eleven (61%) received ≥3 prior therapies. Dose-limiting toxicities were Grade 3 ALT increase (0.10 mg/kg linifanib) and Grade 1 T-wave inversion (0.25 mg/kg linifanib) requiring dose interruption for >7 days and discontinuation on day 29. The most common linifanib-related AE was hypertension. Other significant treatment-related AEs included proteinuria, fatigue, and palmar-plantar erythrodysaesthesia. Linifanib pharmacokinetics were dose-proportional across 0.10-0.25 mg/kg. Two patients (11.1%) had confirmed partial responses, 12 had a best response of stable disease (11 had stable disease for ≥12 weeks), and four patients were not evaluable due to incomplete data. Four patients (lung cancer, breast cancer, thymic cancer, sarcoma) have continued linifanib for ≥48 weeks (range, 48-96+ weeks). CONCLUSION: Linifanib was well tolerated with promising preliminary clinical activity in Japanese patients. Later-phase global studies examining linifanib efficacy will include Japanese patients.
Subject(s)
Angiogenesis Inhibitors/adverse effects , Antineoplastic Agents/adverse effects , Indazoles/adverse effects , Neoplasms/drug therapy , Phenylurea Compounds/adverse effects , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Adult , Aged , Angiogenesis Inhibitors/pharmacokinetics , Antineoplastic Agents/pharmacokinetics , Dose-Response Relationship, Drug , Drug Tolerance , Female , Humans , Indazoles/pharmacokinetics , Male , Membrane Proteins/biosynthesis , Middle Aged , Neoplasms/mortality , Phenylurea Compounds/pharmacokineticsABSTRACT
Monobenzyl ether of hydroquinone (MBEH) is a Food and Drug Administration approved drug used for depigmentation therapy of advanced vitiligo. Here, the working mechanism of MBEH is explored in comparison to 4-tertiary butyl phenol (4-TBP), a known causative agent for occupational vitiligo mediating apoptotic melanocytic death. Cytotoxic experiments reveal that similar to 4-TBP, MBEH induces specific melanocyte death. To compare death pathways initiated by 4-TBP and MBEH, classical apoptotic hallmarks were evaluated in treated melanocytes. MBEH induced cell death without activating the caspase cascade or DNA fragmentation, showing that the death pathway is non-apoptotic. Release of High Mobility Group Box-1 protein by MBEH-treated melanocytes and ultrastructural features further confirmed a necrotic death pathway mediated by MBEH. A negative correlation between MBEH-induced cell death and cellular melanin content supports a cytoprotective role for melanin. Moreover, MBEH exposure upregulated the levels of melanogenic enzymes in cultured melanocytes and skin explants, whereas 4-TBP reduced the expression of the same. In summary, exposure to MBEH or 4-TBP has profoundly different consequences for melanocyte physiology and activates different death pathways. As the mode of cell death defines the nature of the immune response that follows, these findings help to explain the relative efficacy of these agents in mediating depigmentation.