A phase 2 clinical trial of neoadjuvant anti-PD-1 ab (Toripalimab) plus axitinib in resectable mucosal melanoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9512-9512
Author(s):  
Chuanliang Cui ◽  
Xuan Wang ◽  
Bin Lian ◽  
Lu Si ◽  
Zhihong Chi ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Tumor Cells ◽  
Response Rate ◽  
Mucosal Melanoma ◽  
Pathologic Response ◽  
Phase 2 ◽  
Viable Tumor ◽  
Pathologic Response Rate ◽  
Clinical Trial Information

9512 Background: The outcome of patients (pts) with resectable mucosal melanoma (MM) is still poor. Toripalimab combined with axitinib has shown impressive results in metastatic MM with an ORR of 48.3% and a median PFS of 7.5 months in a phase 1b trial. It was hypothesized that this combination therapy might cause pathologic response in neoadjuvant setting for resectable MM, so we conducted this single arm phase 2 trial. Methods: Eligible pts were adults (aged 18 to 75) with histologically confirmed resectable (localized or regional lymph node metastasis) MM disease. Exclusion criteria included ocular or unknown primary melanoma, distant metastatic disease or previous use of anti PD-1 ab. Pts received toripalimab 3 mg/kg Q2W plus axitinib 5 mg BID for 8 weeks as neoadjuvant therapy, then surgery and the adjuvant toripalimab 3 mg/kg Q2W starting 2±1week after surgery for totally 52 weeks. The primary end point is pathologic response rate according to the International Neoadjuvant Melanoma Consortium (pCR+pPR, pCR is defined as the complete absence of residual viable tumor and pPR ≤ 50% of viable tumor cells). The secondary end point is RFS in the ITT population. Clinical trial information: NCT04180995. Results: From Aug 2019 to Dec 2020, 21 pts have been eligible and enrolled. Basic characteristics: median age 62 years; M: F 28.6% : 71.4%; primary sites 8 femal genital(1urethra, 7vagina), 5 esophagus, 4 ano-rectal, 4 head & neck(3 nasal,1 oral), in which 47.6% localized disease (T3/4 60%), 52.4% regional lymphatic disease; Gene mutation: 4 cKit (1 amplification), 2 Nras,1 Braf (N581), 1mTOR. This therapy was tolerable with grade 3-4 treatment related AEs of 23.8% (liver dysfunction 14.3%, hyperglycemia 9.5% and hypertension 4.8%). 13 pts had received surgeries (local excision 30.8%, wide excision ± CLND72.7%)and 5 pts still in neoadjuvant treatment. One patient was inoperable for bone metastasis, and 2 pts withdrew for covid 19 epidemic. At a median follow up time of 59 weeks, the pathologic response rate was 28.6% (4/14, 2 pCR, 2pPR). Of the post-surgical specimens, 61.5% (8/13) showed significant TIL infiltration, with 38.5% Brisk and 23.1% Nonbrisk according to the definition of AJCC 8th edition. Plenty of plasma cells, histiocyte and pigment with hyaline fibrosis were also found in responders. No recurrence or metastasis was observed in responders until now, with a RFS reaching more than 58weeks. 5 pts with pNR( > 50% viable tumor cells) got disease progression, with 1 local recurrence, 1 regional lymphatic metastasis, and 3 distant metastases. The median RFS has not been reached. Conclusions: Neoadjuvant toripalimab plus axitinib in resectable MM has shown promising pathologic responses with good tolerance, which supports further investigation of neoadjuvant therapies in MM. Survival is still in follow-up. Clinical trial information: NCT04180995.

Update on KEYNOTE-199, cohorts 1-3: Pembrolizumab (pembro) for docetaxel-pretreated metastatic castration-resistant prostate cancer (mCRPC).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 104-104 ◽  
Author(s):  
Emmanuel S. Antonarakis ◽  
Josep M. Piulats ◽  
Marine Gross-Goupil ◽  
Jeffrey C. Goh ◽  
Ulka N. Vaishampayan ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Response Rate ◽  
Phase 2 ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Phase 2 Study ◽  
Previously Treated ◽  
Grade 3 ◽  
Clinical Trial Information

104 Background: The KEYNOTE-199 multicohort phase 2 study (NCT02787005) showed that pembro monotherapy has antitumor activity and acceptable safety in patients (pts) with mCRPC previously treated with a next-generation hormonal agent (NHA) and docetaxel in cohort 1 (C1) (RECIST-measurable, PD-L1+ disease), C2 (RECIST-measurable, PD-L1− disease), and C3 (bone-predominant disease, irrespective of PD-L1). Updated results with additional follow-up for C1-3 are presented. Methods: Pts previously received ≥1 NHAs and 1 or 2 chemotherapies, including docetaxel. Pts received pembro 200 mg Q3W for 35 cycles or until progression or intolerable toxicity. Primary end point was ORR. Key secondary end points were DCR, DOR, PSA (≥50%) response rate, rPFS, OS, and safety. Results: Of 258 pts enrolled (C1=133; C2=67; C3=58), 6 completed (C1=4; C3=2) and 252 discontinued (C1=129; C2=67; C3=56) therapy, primarily due to progression (C1=106; C2=61; C3=45). Median follow-up was 9.6 mo (C1, 9.5; C2, 7.9; C3, 14.2). ORR (95% CI) for pts with measurable disease was 6% (2.6-11.5) in C1 and 3% (0.4-10.4) in C2 (Table; includes other efficacy results). Treatment-related AEs of any grade/grade 3-5 occurred in 57%/16% in C1, 60%/15% in C2, and 71%/17% in C3. 1 pt in each cohort died of a treatment-related AE (C1, sepsis; C2, unknown; C3, immune-related pneumonitis). Conclusions: With additional follow-up, pembro monotherapy continued to show antitumor activity and disease control in pts with RECIST-measurable and bone-predominant mCRPC previously treated with both NHA and docetaxel. Pts experienced durable responses. Safety was consistent with the known safety profile of pembro. Clinical trial information: NCT02787005. [Table: see text]

A pilot study of local injection of TNFerade biologic in addition to neo-adjuvant chemoradiation for the treatment of primary and recurrent rectal cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14585-14585
Author(s):  
K. A. Camphausen ◽  
M. Quezado ◽  
D. Citrin ◽  
J. F. Pingpank ◽  
B. Wood ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Local Recurrence ◽  
Response Rate ◽  
External Beam Radiotherapy ◽  
Inducible Promoter ◽  
Sphincter Preservation ◽  
Pathologic Response ◽  
Entire Area ◽  
Viable Tumor ◽  
Pathologic Response Rate

14585 Background: Rectal cancer presents unique therapeutic considerations due to competing concerns regarding sphincter preservation and local recurrence. Treatments using pre-operative chemoradiation are employed to decrease local recurrence and improve the probability of sphincter preservation. Agents, which improve the pathologic response rate may be of further benefit. Methods: TNFerade biologic is a replication deficient adenovirus expressing human TNF-alpha driven by a radiation inducible promoter. TNFerade biologic (4X10e10 pfu) is injected locally into rectal tumors once a week for 5 weeks. Patients receive concurrent chemoradiation utilizing oral capecitabene (937.50 mg/m2 BID, Monday-Friday) and external beam radiotherapy (1.8 Gy/day, 5 days per week to a total dose of 45 Gy). A boost dose of 5.4–9 Gy is delivered to sites of gross disease. After treatment, patients recover for 6–9 weeks before surgery. Patients are scored prior to the start of neo-adjuvant therapy for the feasibility of a sphincter preserving operation versus an abdominal perineal resection (APR). Following surgery the specimen (entire area submitted for processing) is examined for the percent of viable tumor remaining. The goal of the study is to show a target pathologic response rate of <10% viable tumor in more than 30% of patients treated. Results: Six patients have been treated (4M, 2F). There has been no toxicity attributable to the TNFerade biologic, and the chemoradiation has been well tolerated with only mild, expected toxicities. Five of the six patients have undergone surgery (one is awaiting surgery). Three of these five patients were thought to require an APR prior to treatment due to the size and location of their tumor. All five patients have successfully undergone sphincter- preserving operations. On examination of the five specimens, 3 had less than 5% viable tumor while 2 had greater than 50% viable tumor. All resections were margin negative. The target pathologic response rate of <10% viable tumor was achieved in 60% of the patients evaluated. Conclusion: The addition of TNFerade biologic to pre-operative chemoradiation was well tolerated and a prospective randomized trial comparing the addition of this agent to chemoradiation is warranted. No significant financial relationships to disclose.

Camrelizumab plus chemotherapy as neoadjuvant therapy for resectable, locally advanced esophageal squamous cell carcinoma (NIC-ESCC2019): A multicenter, open-label, single-arm, phase 2 study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4028-4028
Author(s):  
Jingpei Li ◽  
Jun Liu ◽  
Zhuoyi Li ◽  
Fei Cui ◽  
Yuan Zeng ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Squamous Cell Carcinoma ◽  
Neoadjuvant Chemotherapy ◽  
Esophageal Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Primary Tumor ◽  
Pathologic Response ◽  
Pathological Response ◽  
Phase 2 ◽  
Phase 2 Study

4028 Background: Despite multidisciplinary therapies, prognosis of pts with resectable esophageal squamous cell carcinoma (ESCC) remains poor. Combining PD-1 blockade to neoadjuvant chemotherapy might be a feasible and effective strategy. Camrelizumab (an anti-PD-1 antibody) was approved for advanced or metastatic ESCC in the second-line setting and showed improved anti-tumor activity and survival benefit when combined with chemotherapy in multiple advanced tumors. Methods: In this NIC-ESCC2019 phase 2 study, histologically or cytologically confirmed ESCC pts (stage II-IVA) were enrolled to receive two cycles of neoadjuvant chemoimmunotherapy (NIC) with camrelizumab (200 mg on day 1) plus nab-paclitaxel (260 mg/m² in total on day 1 and day 8) and cisplatin (75 mg/m² in total on days 1-3) of each 21-day cycle, followed by esophagectomy. The primary endpoint was complete pathologic response (CPR) rate in the primary tumor. Besides, we also explored the relationship between the tumor genomic profile or primary-tumor microenvironment and the pathological response. Results: Between Jan 17, 2020 and Dec 8, 2020, 56 pts were enrolled. 51 pts underwent surgical resection, and all had complete tumor resection. CPR was achieved in 18 (35.3%; 95% CI, 21.7%-48.9%) pts; 12 (23.5%) pts had major pathologic response (MPR), and 21 (41.2%) had incomplete pathological response (IPR). Of note, 16 (31.4%) pts achieved CPR in both primary tumor and lymph nodes. The objective response rate was 66.7% (95% CI, 40.0-70.4). No in-hospital mortality occurred. The most common treatment-related adverse events (TRAEs) were decreased WBC (20 [36%] of 56 pts), vomiting (19 [34%]), and alopecia (18 [32%]). Grade 3 TRAEs only occurred in 6 (11%) pts, and there were no grade 4 or 5 TRAEs. The most common immune-related AEs included grade 1-2 rash maculo-papular (7 [13%]) and reactive cutaneous capillary endothelial proliferation (5 [9%]). Presence of mutations in CREBBP and KMT2D at treatment-naïve time-point was correlated with non-response group (IPR and stable disease) (CREBBP, p = 0.046; KMT2D, p = 0.047). Among the immune populations, CD8+, CD8+PD-1+ and CD8+PD-L1+ T cells increased significantly after two doses of NIC, especially in the CPR+MPR group (CD8+, p = 0.013; CD8+PD-1+, p < 0.001; CD8+PD-L1+, p = 0.068). Conclusions: The addition of camrelizumab to neoadjuvant chemotherapy in ESCC demonstrated promising efficacy with acceptable toxicity, supporting the further investigation in a randomized phase 3 clinical trial. Clinical trial information: NCT04225364. [Table: see text]

scholarly journals 548 Phase 2 study of FLX475 in combination with ipilimumab in advanced melanoma

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A578-A578
Author(s):  
Rakesh Goyal ◽  
Nicole Nasrah ◽  
Dan Johnson ◽  
William Ho
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
Antitumor Activity ◽  
Regulatory T Cells ◽  
Response Rate ◽  
Advanced Melanoma ◽  
Phase 2 ◽  
Car T Cells ◽  
Phase 2 Study ◽  
Car T

BackgroundRegulatory T cells (Treg) can dampen antitumor immune responses in the tumor microenvironment (TME) and have been shown to correlate with poor clinical outcome. Translational studies have demonstrated an accumulation of Treg in tumors after treatment with immunotherapies including CAR-T cells and anti-CTLA-4, which could potentially reflect a mechanism of adaptive immune resistance.1–2 CCR4, the receptor for the chemokines CCL17 and CCL22, is the predominant chemokine receptor on human Treg and is responsible for the migration and accumulation of Treg in the TME. 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 antitumor efficacy as a single agent and in combination with checkpoint inhibitors, including anti-CTLA-4.3 In a first-in-human trial conducted in healthy volunteers, the oral CCR4 antagonist FLX475 was demonstrated to be well tolerated with outstanding pharmacokinetic and pharmacodynamic properties.4 An ongoing Phase 1/2 clinical trial of FLX475 is examining the safety and preliminary antitumor activity of FLX475 as monotherapy and in combination with pembrolizumab in subjects with several types of advanced cancer.5 Given the preclinical data demonstrating a significant enhancement of the antitumor activity of anti-CTLA-4 when combined with FLX475, a Phase 2 study investigating the combination of FLX475 and ipilimumab is now being conducted in subjects with advanced melanoma.MethodsThis clinical trial is a Phase 2, multicenter, open-label, single-arm study to determine the antitumor activity of FLX475 in combination with ipilimumab in subjects with advanced melanoma previously treated with an anti-PD-1 or anti-PD-L1 agent. The primary objectives of the study are to evaluate objective response rate, and the safety and tolerability of this combination. The study will first examine the safety of the combination of the 100 mg PO QD recommended Phase 2 dose of FLX475 and the approved 3 mg/kg IV Q3W dose of ipilimumab as part of a safety run-in phase, prior to examining the degree of antitumor activity in approximately 20 subjects. Evidence of an overall response rate (ORR) notably greater than the expected ORR of ipilimumab monotherapy alone in such subjects, which has been shown to be approximately 14%,6 would provide preliminary clinical evidence in support of the clinical hypothesis that CCR4 blockade by FLX475 can significantly enhance the antitumor activity of an anti-CTLA-4 checkpoint inhibitor.Trial RegistrationClinicalTrials.gov Identifier: NCT04894994ReferencesO’Rourke D, Nasrallah M, Desai A, Melenhorst J, Mansfield K, Morrissette J, Martinez-Lage M, Brem S, Maloney E, Shen A, Isaacs R, Mohan S, Plesa G, Lacey S, Navenot J, Zheng Z, Levine B, Okada H, June C, Brogdon J, Maus M. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci Transl Med 2017;9:eaaa0984. doi: 10.1126/scitranslmed.aaa0984.Sharma A, Subudhi S, Blando J, Vence L, Wargo J, Allison JP, Ribas A, Sharma P. Anti-CTLA-4 immunotherapy does not deplete FOXP3+ regulatory T cells (Tregs) in human cancers-Response. Clin Cancer Res 2019;25:1233–1238.Marshall L, Marubayashi S, Jorapur A, Jacobson S, Zibinsky M, Robles O, Hu D, Jackson J, Pookot D, Sanchez J, Brovarney M, Wadsworth A, Chian D, Wustrow D, Kassner P, Cutler G, Wong B, Brockstedt D, Talay O. Tumors establish resistance to immunotherapy by regulating Treg recruitment via CCR4. J Immunother Cancer 2020;8:e000764.van Marle S, van Hoogdalem E, Johnson D, Okal A, Kassner P, Wustrow D, Ho W, Smith S. Pharmacokinetics, pharmacodynamics, and safety of FLX475, an orally-available, potent, and selective small-molecule antagonist of CCR4, in healthy volunteers. J Immunother Cancer 2018; 6(Suppl 1):P484(SITC 2018).Powderly J, Chmielowski B, Brahmer J, Piha-Paul S, Bowyer S, LoRusso P, Catenacci D, Wu C, Barve M, Chisamore M, Nasrah N, Johnson D, Ho W. Phase I/II dose-escalation and expansion study of FLX475 alone and in combination with pembrolizumab in advanced cancer. Journal of Clinical Oncology 2020;38(15_suppl): TPS3163 (ASCO 2020).Long G, Mortier L, Schachter J, Middleton M, Neyns B, Sznol M, Zhou H, Ebbinghaus S, Ibrahim N, Arance A, Ribas A, Blank C and Robert C. Society for Melanoma Research 2016 Congress. Pigment Cell & Melanoma Research 2017;30:76–156.Ethics ApprovalThis study has been approved by the Institutional Review Board at each investigational site.

scholarly journals Phase 3 Study of Pomalidomide with Cyclophosphamide and Dexamethasone Versus Pomalidomide and Dexamethasone in Asian Patients with Relapsed/Refractory Myeloma (RRMM) - Interim Analysis of a Trial By the Asian Myeloma Network (AMN)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 1-1
Author(s):  
Wee-Joo Chng ◽  
Xinhua Li ◽  
Cindy Lin ◽  
Jin Seok Kim ◽  
Hiroshi Handa ◽  
...  
Keyword(s):  
Interim Analysis ◽  
Research Funding ◽  
Response Rate ◽  
Prior Exposure ◽  
Phase 2 ◽  
Asian Patients ◽  
Phase 2 Study ◽  
Grade 3 ◽  
Experienced Grade

Background Pomalidomide is an immunomodulatory drug that has been approved for the treatment of relapse refractory myeloma. A previous small randomized phase 2 study in the United States showed that combination of Pomalidomide, cyclophosphamide and dexamethasone induce a greater response rate than pomalidomide and dexamethasone1. In our prior study, AMN0012, we should that in patients with sub-optimal response to pomalidomide and dexamethasone, the addition of cyclophosphamide can increase response resulting in improvement of progression free survival. In the current study, we seek to randomize Asian patients with RRMM between PCD and PD to confirm the benefit of PCD. Method We conducted a prospective randomized trial of pomalidomide (4mg daily for 21 days followed by 7 days rest) plus dexamethasone 40mg once weekly for 4 weeks with or without cyclophosphamide (400mg once a week) in patients with relapse and refractory myeloma that has to be refractory to lenalidomide and has prior exposure to proteasome inhibitors. Each cycle is 4 weeks. Patients from Singapore, Japan and Korea (NCT03143049) were included in this Asian Myeloma Network trial. The trial was started in Sep 2017 and is still ongoing. To date, 53 patients have been recruited so far. This interim report presents data available up till the data cut-off date of 24 June 2020. Results Forty-six patients have available base line information and safety data and is included in this interim analysis. 50% of patients are male and median age of the cohort is 68 years old. 39% and 28% of patients are International Stage System (ISS) stage 2 and 3 respectively. 20% of patients have abnormal creatinine clearance. Median prior line of treatment is 3. All patients are refractory to lenalidomide and 96% have prior exposure to bortezomib. In addition, 12 patients (26%) and 5 (11%) have been treated with Carfilzomib and Ixazomib respectively. 15 (33%) patients had prior high dose melphalan and autologous stem cell transplant. 20 (44%) patients required dose reduction of pomalidomide, cyclophosphamide or dexamethasone. 89% of patients experience adverse events (AEs) of any grade. Of the 297 episodes of AEs, 43% are grade 3 or higher, with 50% of these episodes related to the study drugs. 57% of patients experienced serious AEs (SAEs) of any grade. Of the 74 episodes of SAE, 89% are grade 3 or higher, with 49% of these episodes related to the study drugs. Almost all of these events are related to cytopenias and infections. 20 (44%) of the patients develop grade 3 neutropenic fever and 9 (20%) patients have grade 3 or higher pneumonia. Only 1 patient experienced grade 3 peripheral neuropathy, 1 patient develop grade 3 pulmonary embolism, 1 patient developed grade 3 venous thromboembolism, and 1 patient experienced grade 3 renal impairment. At a median follow-up of 10.9 months, 9 of the 46 patients have died, and 21 have progressed. Three patients withdrew due to toxicity. While the overall response of the study population is not part of this interim analysis, we assessed the response of patients from the National University Cancer Institute, Singapore which has the highest number of patients recruited to get an idea of the therapeutic efficacy. Of the 14 patients recruited at NCIS, 1 patient achieved CR, 3 VGPR, 7 PR, producing a response rate of 79%. Conclusion In this interim analysis of a prospective randomized study of pomalidomide and dexamethasone with or without cyclophosphamide in Asian patients, we demonstrated the feasibility and efficacy of this combination. Longer follow-up and final analysis of the study will be needed to ascertain the therapeutic advantage of PCD over PD in relapse and refractory myeloma that is refractory to lenalidomide. References 1. Baz RC, Martin TG 3rd, Lin HY, Zhao X, Shain KH, Cho HJ, Wolf JL, Mahindra A, Chari A, Sullivan DM, Nardelli LA, Lau K, Alsina M, Jagannath S. Randomized multicenter phase 2 study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma. Blood. 2016 May 26;127(21):2561-8. 2. Soekojo CY, Kim K, Huang SY, Chim CS, Takezako N, Asaoku H, Kimura H, Kosugi H, Sakamoto J, Gopalakrishnan SK, Nagarajan C, Wei Y, Moorakonda R, Lee SL, Lee JJ, Yoon SS, Kim JS, Min CK, Lee JH, Durie B,Chng WJ. 3. Pomalidomide and dexamethasone combination with additional cyclophosphamide in relapsed/refractory multiple myeloma (AMN001)-a trial by the Asian Myeloma Network. Blood Cancer J. 2019 Oct 8;9(10):83. Disclosures Chng: Novartis: Honoraria; Abbvie: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Kim:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

Randomized trial of chemoendocrine therapy started before or after surgery for treatment of primary breast cancer.

1995 ◽  
Vol 13 (3) ◽  
pp. 547-552 ◽  
Author(s):  
T J Powles ◽  
T F Hickish ◽  
A Makris ◽  
S E Ashley ◽  
M E O'Brien ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
Adjuvant Therapy ◽  
Randomized Trial ◽  
Response Rate ◽  
Neoadjuvant Treatment ◽  
Operable Breast Cancer ◽  
Chemoendocrine Therapy ◽  
Primary Operable Breast Cancer

PURPOSE To evaluate in a randomized clinical trial systemic chemoendocrine therapy used as primary (neo-adjuvant) treatment before surgery in women with primary operable breast cancer. PATIENTS AND METHODS Patients aged less than 70 years with clinically palpable, primary operable breast cancer diagnostically confirmed by fine-needle aspiration cytology (FNAC) and suitable for treatment with surgery, radiotherapy, cytotoxic chemotherapy, and tamoxifen were considered eligible. Patients randomized to neoadjuvant treatment received four cycles of chemo-therapy for 3 months before surgery followed by another four cycles after surgery, and were compared with patients randomized to adjuvant therapy who received eight cycles of chemotherapy over 6 months after surgery. RESULTS Of 212 patients who were randomized to receive either adjuvant (n = 107) or neoadjuvant (n = 105) chemoendocrine therapy, 200 are now assessable for response. The two groups are comparable for age, menopausal status, disease stage, and surgical requirements. The overall clinical response rate was 85%, with a complete histologic response rate of 10%. There was a significant reduction in the requirement for mastectomy in patients who received neoadjuvant treatment (13%) as compared with those who received adjuvant therapy (28%) (P < .005). Symptomatic and hematologic acute toxicity was low and similar for adjuvant and neoadjuvant therapy. The median follow-up period for patients in this trial is 28 months, during which time four patients have relapsed locally and 20, including one of the local relapses, have developed metastatic disease, 19 of whom have died. The follow-up period is too brief to evaluate relapse rate or survival duration. CONCLUSION This trial confirms previous reports of a high rate of response to neoadjuvant therapy, but is the first to include small primary cancers and to show, in the context of a randomized trial, a reduction in the requirement for mastectomy. Until disease-free and overall survival data are available from the larger National Surgical Adjuvant Breast and Bowel Project (NSABP)-18 trial, such neoadjuvant treatment cannot be recommended outside of a clinical trial.

Long-Term Follow-Up of Patients Treated with Bortezomib Alone and in Combination with Dexamethasone as Frontline Therapy for Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 796-796 ◽  
Author(s):  
Sundar Jagannath ◽  
Brian G.M. Durie ◽  
Jeffrey Lee Wolf ◽  
Elber S. Camacho ◽  
David Irwin ◽  
...  
Keyword(s):  
Stem Cell ◽  
Survival Rate ◽  
Median Time ◽  
Response Rate ◽  
Sensory Neuropathy ◽  
High Response Rate ◽  
High Dose ◽  
Phase 2 ◽  
Frontline Therapy

Abstract Introduction: Novel therapeutic agents, such as bortezomib (VELCADE®; btz), thalidomide, and lenalidomide, are being used in combination with dexamethasone (dex) as frontline therapies in MM. Phase 2 and 3 trials with limited follow-up have reported a high response rate and feasibility of high-dose therapy and stem cell transplantation (HDT-SCT). Here we present longer follow-up on our phase 2 trial of btz±dex as frontline therapy. Methods: Patients (pts) with measurable disease and KPS ≥50% received btz 1.3mg/m2 on days 1, 4, 8 and 11 of a 3-week cycle for up to 6 cycles. Oral dex 40mg was added on the day of and day after btz for pts achieving &lt; partial response (PR) after 2 cycles or &lt; complete response (CR) after 4 cycles. Responses were assessed using European Group for Blood and Marrow Transplantation criteria, with the addition of near CR (nCR; CR but positive immunofixation). Results: 48 pts were accrued and were evaluable for response; a further 2 registered on the trial declined to proceed. Median age was 60 years, 46% were male, 64% had IgG and 21% IgA, and 50% were Durie-Salmon stage III. At the end of btz±dex treatment, overall response rate (ORR; CR+nCR+PR) was 90% with 19% CR/nCR; an additional 8% achieved a minimal response (MR). Response to btz alone was rapid; response rate by end of cycle 2 was 50%, including 10% CR/nCR. Dex was added for 36 (75%) pts: 17 at cycle 3, 18 at cycle 5, and 1 at cycle 6. Addition of dex improved best responses to btz in 23 (64%) pts, with 12 improving from stable disease to MR or PR, 9 from MR to PR, 1 from PR to nCR, and 1 from nCR to CR. Median time to best response was 1.9 months. For all 48 pts, with a median follow-up of 24 months, median time to alternative therapy (TTAT) was 7 months (range: 2–25; this includes pts who went on to HDT-SCT), and median overall survival (OS) has not been reached; 1-year survival rate was 90%. For pts not proceeding to HDT-SCT, median TTAT was 22 months, median OS has not been reached; 1-year survival rate was 80%. 23/48 pts proceeded to HDT-SCT. Median CD34+ harvest was 12.6 x 106 cells/kg (range: 5.1–40.4 x 106) from a median of 2 collection days (range: 1–8). All pts had complete hematologic recovery; median time to neutrophil (ANC &gt;1000/mm3) and platelet (&gt;100,000/mm3) engraftment was 11 days (range: 8–13) and 17 days (range: 10–98), respectively. In the 23 HDT-SCT pts, median TTAT and OS have not been reached; post-transplant 1-year survival rate was 90%. The most common grade ≥2 adverse events for btz±dex were sensory neuropathy/neuropathic pain (37%), fatigue (20%), constipation (16%), nausea (12%), and neutropenia (12%). Two pts developed grade 4 events (1 neutropenia, 1 thrombocytopenia). Conclusion: Btz±dex is an effective frontline therapy for MM, with an ORR of 90%, including 19% CR/nCR, and OS rate of 80% at 1 year. The treatment is well tolerated and toxicities were manageable and reversible. Addition of dex to btz provides improved responses. TTAT for patients not undergoing HDT-SCT was 22 months. The regimen does not prejudice subsequent HDT-SCT; stem cell harvest and engraftment were successful in all pts proceeding to transplant. Consolidation with HDT-SCT further increases the response rate and durability of response. Btz+dex is being compared to VAD as induction therapy prior to HDT-SCT in a phase 3 study.

A Phase 2 Study of Bortezomib Combined with Reinduction Chemotherapy in Children and Young Adults with Recurrent, Refractory or Secondary Acute Myeloid Leukemia: A Children's Oncology Group (COG) Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3580-3580 ◽  
Author(s):  
Terzah M. Horton ◽  
John Perentesis ◽  
Alan S. Gamis ◽  
Todd A. Alonzo ◽  
Robert B. Gerbing ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Acute Myeloid Leukemia ◽  
Study Design ◽  
Proteasome Inhibitor ◽  
Myeloid Leukemia ◽  
Response Rate ◽  
Dose Finding ◽  
Phase 2 ◽  
Phase 2 Study ◽  
Acute Myeloid

Abstract Abstract 3580 Purpose: Bortezomib is a 26S proteasome inhibitor that is effective for the treatment of multiple myeloma and indolent lymphomas in adults. Bortezomib at a dose of 1.3 mg/m2 is well tolerated in pediatric patients as a single agent and in combination with cytotoxic chemotherapy. In vitro studies indicate that the proteasome inhibitor bortezomib sensitizes bulk myeloid leukemia and leukemia initiating cells (LIC) to chemotherapy. This Phase 2 study examined the tolerability and efficacy of bortezomib combined with reinduction chemotherapy for relapsed pediatric acute myeloid leukemia (AML). Patients and Methods: This study was a two-arm, non-randomized, open label clinical trial in which patients received bortezomib twice weekly (1.3 mg/m2 on days 1, 4, and 8) in a 28-day cycle. Arm A (for patients with prior anthracycline exposure <400mg/m2) combined bortezomib with idarubicin (12 mg/m2 on days 1–3) and cytarabine (100mg/m2 on days 1–7). Arm B (for patients with prior anthracycline exposure >400 mg/m2) combined bortezomib with cytarabine (1000mg/m2 q12h on days 1–5) and etoposide (150 mg/m2on days 1–5). Arm B included an initial dose finding phase (n=12) which determined that bortezomib at 1.3 mg/m2/dose was safe to combine with cytarabine/etoposide. Bortezomib was then tested in a 2-stage efficacy phase for both arms. A second cycle of protocol therapy was allowed for patients with a response of at least stable disease. Results: The clinical trial enrolled a total of 52 patients for a total number of 61 cycles of therapy. Arm A enrolled 18 patients (16 eligible, 14 evaluable) and Arm B enrolled 34 patients (n=12 dose finding phase, n=22 efficacy phase (21 evaluable)) for a total of 24 patients evaluable for efficacy in Arm B. The addition of bortezomib to chemotherapy was tolerable in both arms. Severe toxicities included febrile neutropenia (29%) and transient hypokalemia (29%). Although tolerable, both Arm A and Arm B were closed after stage 1 of a two stage study design for failure to meet the efficacy threshold. Arm A response rate was 28% (3 CR and 1 CRp) and Arm B response rate was 42% (8 CR and 2 CRp). Although bortezomib was tolerated in both arms, response rates were adversely affected by a delay in neutrophil count recovery (ANC). Four patients in Arm A and 1 patient in Arm B had a complete response with delayed neutrophil recovery (CRi) which was considered a treatment failure in the study design. If a response of CRi had been included as a treatment success, both Arms A and B would have continued into the second stage of efficacy assessment. The 2-year overall survival (OS) for all evaluable patients was 35 ± 21%, and there was no difference in OS between the two treatment arms (Figure 1). Conclusion: Bortezomib is tolerable when added to chemotherapy regimens for children with relapsed/refractory or treatment-related AML. The overall response to the bortezomib containing chemotherapy regimens in the patients enrolled on the efficacy phase (CR + CRp + CRi) (50%) was similar to other salvage regimens for childhood acute myeloid leukemia. Bortezomib, however, did not improve either the CR rate or the OS of this patient cohort. Disclosures: Off Label Use: Testing of bortezomib for pediatric AML in the context of a phase 2 clinical trial.

Progression after the next line of therapy (PFS2) and updated OS among patients (pts) with advanced NSCLC and PD-L1 tumor proportion score (TPS) ≥50% enrolled in KEYNOTE-024.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9000-9000 ◽  
Author(s):  
Julie R. Brahmer ◽  
Delvys Rodriguez-Abreu ◽  
Andrew George Robinson ◽  
Rina Hui ◽  
Tibor Csõszi ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Advanced Nsclc ◽  
Anticancer Therapy ◽  
Egfr Mutations ◽  
First Line ◽  
Kaplan Meier ◽  
Line Of Therapy ◽  
Clinical Trial Information ◽  
Platinum Doublet

9000 Background: In KEYNOTE-024 (NCT02142738), pembrolizumab (pembro) was superior to chemotherapy (chemo) as first-line (1L) therapy for advanced NSCLC with PD-L1 TPS ≥50% and no sensitizing EGFR mutations or ALK translocations. After a median follow-up of 11.2 mo, HR was 0.50 for PFS by independent central radiologic review ( P< 0.001) and 0.60 for OS ( P= 0.005). Here we present PFS2 and updated OS. Methods: 305 pts were randomly assigned to pembro 200 mg Q3W (n = 154) or investigator (INV)-choice platinum-doublet chemo with optional pemetrexed maintenance for nonsquamous histology (n = 151). Pts in the chemo arm could cross over to pembro upon PD. Poststudy anticancer therapy and INV-assessed outcomes were collected. Kaplan-Meier PFS2 and OS were calculated in all allocated pts. PFS2 was defined as time from randomization to PD per INV after start of 2L+ therapy or death, whichever occurred first; pts alive and without 2L+ PD were censored at last known survival. Kaplan-Meier OS was defined as time from randomization to death. There was no adjustment for multiplicity (cutoff: Jan 5, 2017). Results: 2L+ therapy was received by 48 (31.2%) pts in the pembro arm and 97 (64.2%) in the chemo arm, including 80 pts who crossed over from chemo to pembro per protocol and 14 pts who received anti–PD-1 therapy outside of crossover. 56 (36%) 1L pembro pts were on 1L pembro therapy or in follow-up as of data cutoff. Updated median OS and PFS2 results are in the Table. Conclusions: Fewer pembro pts received 2L+ therapy vs chemo pts because of the significant improvement in PFS observed for pembro in the 1L setting. Median PFS2 was substantially improved for pembro (not reached [NR]) vs chemo (8.6 mo). Updated OS with median follow-up of 19 mo maintained consistent superiority of 1L pembro, despite increased crossover from 1L chemo. Clinical trial information: NCT02142738. [Table: see text]

First-line (1L) avelumab treatment in patients (pts) with metastatic Merkel cell carcinoma (mMCC): Preliminary data from an ongoing study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9530-9530 ◽  
Author(s):  
Sandra P. D'Angelo ◽  
Jeffrey Russell ◽  
Jessica Cecile Hassel ◽  
Celeste Lebbe ◽  
Bartosz Chmielowski ◽  
...  
Keyword(s):  
Safety Profile ◽  
Response Rate ◽  
Objective Response ◽  
Durable Response ◽  
Phase 2 Study ◽  
Grade 3 ◽  
Related Reaction ◽  
Unacceptable Toxicity ◽  
Clinical Trial Information

9530 Background: MCC is a rare, aggressive skin cancer. Avelumab is a fully human anti–PD-L1 antibody. In a phase 2 study in pts with distant mMCC who progressed after prior chemotherapy (JAVELIN Merkel 200; NCT02155647), avelumab showed a manageable safety profile and durable responses, including an objective response rate (ORR) of 31.8%, estimated 6-month durable response rate of 29%, and 6-month overall survival rate of 69%. Here, we report preliminary results from a separate cohort of pts with chemotherapy-naïve mMCC enrolled in the same study. Methods: Eligible pts with mMCC and no prior systemic treatment for metastatic disease received avelumab 10 mg/kg Q2W until confirmed progression, unacceptable toxicity, or withdrawal. Tumors were assessed every 6 weeks (RECIST v1.1). Adverse events (AEs) were assessed by NCI CTCAE v4.0. Results: As of Dec 30, 2016, 29/112 planned pts had been enrolled. Median age was 75.0 years (range 47–87). Median treatment duration was 8.1 weeks (range 2.0–37.9). Of 16 pts with ≥3 months of follow-up, unconfirmed ORR was 68.8% (95% CI 41.3–89.0) with CR in 18.8%; confirmed ORR was 56.3% (95% CI 29.9–80.2; 1 unconfirmed PR with discontinuation). Of 25 pts with ≥6 weeks of follow-up, unconfirmed ORR was 64.0% (95% CI 42.5–82.0). All responses were ongoing at last follow-up, including in 5/5 pts with ≥6 months of follow-up (potential to confirm responses). 20/29 pts (69.0%) had a treatment-related AE (TRAE), including grade 3–4 TRAE in 5 pts (17.2%). TRAEs led to discontinuation in 5 pts (17.2%): 2 pts with infusion-related reaction, and 1 pt each with elevated AST and ALT, cholangitis, and paraneoplastic syndrome. There were no treatment-related deaths. 21/29 pts (72.4%) remain on treatment. Conclusions: In initial results from a cohort of chemotherapy-naïve pts with mMCC, avelumab was associated with early responses and a manageable safety profile, consistent with findings for second-line or later avelumab treatment in a previous cohort. These results suggest that responses mature to become durable and the use of 1L avelumab may increase the probability of response vs later-line treatment. Enrollment and follow-up in this 1L cohort are ongoing. Clinical trial information: NCT02155647.

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