Long-term Follow-up Of Phase Research Articles

Long-Term Follow-Up of Phase I Trial of Oncolytic Adenovirus-Mediated Cytotoxic and Interleukin-12 Gene Therapy for Treatment of Metastatic Pancreatic Cancer.

The long-term follow-up findings of the phase I trial evaluating the efficacy of oncolytic adenovirus-mediated cytotoxic and interleukin-12 gene therapy in metastatic pancreatic cancer (mPC) seem very promising. The study employed a replication-competent Adenovector in combination with chemotherapy in a dose-escalation format. The trial demonstrated a clinically meaningful median overall survival (OS) benefit, with patients in the highest dose cohort exhibiting an impressive median OS of 18.4 months. This contrasts starkly with patients receiving lower doses who experienced a median OS of 4.8 and 3.5 months, respectively. Remarkably, subject number 10, who received the highest dose, demonstrated an extraordinary survival of 59.1 months, presenting a compelling case for further exploration. Additionally, this patient displayed complete responses in lung and liver metastases, a rare occurrence in mPC treatment. Statistical analyses supported the observed survival benefit. The unprecedented OS results emphasize the potential of this treatment strategy and pave the way for future investigations into this promising gene therapy approach.

Continued Excellent Outcomes in Previously Untreated Follicular Lymphoma Patients after Treatment with CHOP Plus Rituximab or CHOP Plus (131) Iodine-Tositumomab - Long Term Follow-up of Phase III Randomized Study SWOG S0016

Background: Southwest Oncology Group (SWOG) S0016 was a phase III randomized study that compared safety and efficacy of cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab (CHOP-R) with CHOP followed by consolidation with (131) iodine-tositumomab radioimmunotherapy (CHOP-RIT) for previously untreated follicular lymphoma (FL) patients. As reported previously, the study demonstrated excellent outcomes in both arms with 2-year progression-free survival (PFS) of 76% and 80% and 2-year overall-survival (OS) of 97% and 93% in the CHOP-R and CHOP-RIT arms, respectively. (Press. et al. JCO, 2012) We now report the long term outcome of patients who were treated on the S0016 study.Methods: Between 2001 and 2008, 531 previously untreated advanced follicular lymphoma patients were randomized to receive either 6 cycles of CHOP every 3 weeks with 6 doses of rituximab (CHOP-R) or 6 cycles of CHOP every 3 weeks followed by RIT. Patients with advanced-stage disease (bulky stage II, III or IV) with any pathologic grade (1, 2 or 3) were eligible.Results: Patients on CHOP-R (n=264) and CHOP-RIT (n=267) arms had balanced baseline characteristics including age (median 54.5 vs. 53.4 years), presence of B symptoms (29% vs. 26%), pathologic grade 3 (8% vs. 9%), "high" FLIPI risk group (22% vs. 26%), stage IV disease (59% vs. 63%), elevated β2M (53% vs. 55%), bone marrow involvement (56% vs. 55%) and bulky disease (24% vs. 26%). Objective remissions were documented in 226 of 267 eligible patients treated with CHOP-R (85%) and in 226 of 264 patients with CHOP-RIT (86%). Complete remission (CR) rate was 40% in the CHOP-R and 45% in the CHOP-RIT arm. Neutropenia was the most common adverse event (AE) in both arms (48% vs. 51%). Rate of grade 3-5 AEs were not different except for thrombocytopenia which was more common in the CHOP-RIT group (18% vs. 2%). After a median follow-up of 9.6 years (range 0.1 - 14.4 years), the estimated 10-year PFS was 42% (95% CI: 35.6%, 48.5%) in the CHOP-R arm and 57% (95% CI: 50.5%, 63.2%) in the CHOP-RIT arm (p-value = 0.01). 51% of responders on the CHOP-R arm and 38% of responders on the CHOP-RIT arm have relapsed (p-value= 0.01). The estimated 2-year relapse-free survival was 76% for CHOP-R patients and 81% for CHOP-RIT patients (p-value=0.15). There were 48 deaths in the CHOP+R arm and 59 deaths in the CHOP-RIT arm with an estimated 10-year OS of 82% (95% CI: 76.3%, 86.4%) with CHOP-R and 77% (95% CI: 70.5%, 81.4%) with CHOP-RIT (p-value = 0.18). (Figure-1) During the follow-up, 41 patients (15.4%) in the CHOP-R arm and 37 patients (14%) in the CHOP-RIT arm developed secondary malignancies. MDS/AML were more common in the CHOP-RIT arm (11 patients; 4.2%) compared to CHOP-R arm (5 patients; 1.9%) with a relative risk of 2.2 (95% CI: 0.8-6.3) (P-value 0.12).Conclusion: With almost 10 years of follow-up, patients with FL treated on protocol S0016 show outstanding survival in both CHOP-R and CHOP-RIT arms, and represent the best published long-term outcomes to date in this disease. Indeed, almost half of patients enrolled still remain progression-free, confirming registry experiences. While CHOP-RIT provided significantly longer PFS and lower relapse rate compared to CHOP-R in our study, the OS rate was not different between 2 arms due in part to higher incidence of fatal MDS/AML in the CHOP-RIT group, emphasizing the importance of long-term follow-up, and calling into question the validity of PFS as a surrogate for OS in this setting. Given these outstanding outcomes, we believe chemoimmunotherapy should remain the standard induction approach for patients with high-risk FL until long-term follow-up of alternative approaches demonstrates superiority.Support: NIH/NCI grants CA180888, CA180819, CA180821 and in part by GlaxoSmithKline [Display omitted] DisclosuresShadman:Emergent: Research Funding; Acerta: Research Funding; Gilead: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding. Rimsza:NCI/NIH: Patents & Royalties: L.M. Rimsza is a co-inventor on a provisional patent, owned by the NCI of the NIH, using Nanostring technology for determining cell of origin in DLBCL.. Gopal:Paid Consultancy- Gilead, Janssen, Seattle Genetics, Spectrum, Research funding- Gilead, Janssen, Pfizer, BMS, Merck, Teva, Takeda, Spectrum, Seattle Genetics: Consultancy, Honoraria, Research Funding. Maloney:Juno Therapeutics: Research Funding; Genentech/Roche: Honoraria. Cheson:Gilead: Research Funding; Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Acerta: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Smith:Amgen: Other: Educational lecture to sales force; TGTX: Consultancy; Celgene: Consultancy; Pharmacyclics: Consultancy; Genentech: Consultancy, Other: on a DSMB for two trials ; Portola: Consultancy; Juno: Consultancy; Gilead: Consultancy; AbbVie: Consultancy. Fisher:Seattle Genetics: Consultancy; Gilead: Consultancy; Johnson and Johnson: Consultancy. Friedberg:Bayer: Other: Data Safety Monitoring Committee. Press:Roche / Genentech: Consultancy, Research Funding.

Ponatinib Efficacy and Safety in Patients with the T315I Mutation: Long-Term Follow-up of Phase 1 and Phase 2 (PACE) Trials

Background: Resistance to tyrosine kinase inhibitors (TKIs) in patients (pts) with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) is frequently caused by mutations in the BCR-ABL kinase domain. Ponatinib is the only approved oral TKI that inhibits the T315I mutant, which is uniformly resistant to other TKIs. Here we report long-term follow-up of the efficacy and safety of ponatinib in pts with the T315I mutation at baseline from the Phase 1 (Ph1) and PACE trials. Methods: The Ph1 trial (NCT01207440) evaluated safety and anti-leukemic activity of ponatinib (2-60 mg qd) in pts with CML or Ph+ ALL (N=81); the PACE trial (NCT00660920) evaluated efficacy and safety of ponatinib (45 mg qd) in CML and Ph+ ALL pts (N=449) resistant/intolerant to dasatinib or nilotinib or with the T315I mutation. Data reported are for pts with the T315I mutation at baseline, detected by Sanger sequencing at a central lab. Results: The Ph1 and PACE trials included 19 (29%) and 128 (29%) pts with the T315I mutation, respectively. Median age and median time since diagnosis were 47 and 2.7 years for Ph1, and 53 and 3.6 years for PACE.Pts were heavily pretreated: 89% in Ph1 and 84% in PACE had received ≥2 prior TKIs. As of Jan 6, 2014, median follow-up was 42 (1-59) months in Ph1, and 20 (0.1-40) months in PACE; 58% Ph1 (92% CP-CML) and 33% PACE (52% CP-CML) pts remained on study. Most-common reasons for discontinuation: administrative decision (16%) and progressive disease (16%) for Ph1, and progressive disease (31%) and adverse events (AEs; 13%) for PACE. Of the pooled chronic phase (CP)-CML pts, 75%, 72%, and 61% achieved MCyR, CCyR, and MMR, respectively, with deeper responses (MR4, MR4.5) observed in over a third of the pts (Table). MaHR was achieved in 58%, 27% and 38% of pooled AP-CML, BP-CML and Ph+ ALL pts, respectively. For Ph 1 CP-CML pts, 3-year CCyR duration estimates were 80%. For PACE CP-CML pts, 2-year MCyR/CCyR duration, PFS and OS estimates were 93%/79%, 72% and 82%, respectively. Only 1 CP-CML pt in PACE lost MCyR and 1 transformed to AP-CML. For AP-CML, BP-CML, and Ph+ ALL, estimated OS/PFS at 2 years was 69%/54%, 14%/10%, and 10%/N/A, respectively. The most frequent treatment-emergent AEs (TEAEs) observed in Ph1 CP-CML pts were dry skin (83%), rash (83%), arthralgia (75%), fatigue (75%), headache (67%), abdominal pain (58%), hypertension (58%), hypertriglyceridemia (58%), myalgia (58%), and nausea (58%). None of the 19 serious TEAEs that occurred in Ph1 CP-CML pts occurred in >1 pt. The most common (≥25%) TEAEs in PACE CP-CML pts were rash (48%), dry skin (42%), headache (41%), abdominal pain (39%), nausea (36%), constipation (33%), fatigue (33%), thrombocytopenia (28%), myalgia (28%), hypertension (27%), arthralgia (25%), and upper respiratory tract infection (25%). Most common (≥5 %) serious TEAEs in PACE CP-CML pts were acute myocardial infarction (8%), pancreatitis (8%), atrial fibrillation (6%), coronary artery disease (6%), congestive cardiac failure (5%), pneumonia (5%), cerebral infarction (5%), pyrexia (5%), increased lipase (5%), and dyspnea (5%). Arterial thrombotic events occurred in 1 (8%) Ph1, and 20 (31%) PACE pts. Venous thromboembolic events occurred in 1 (8%) Ph1, and 3 (5%) PACE pts. Despite the higher median dose intensity for T315I CP-CML pts (38 vs 30.8 mg/day overall CP-CML) in PACE, the safety profiles were similar. For CP-CML pts in PACE, responses achieved by 12 months were generally maintained after dose reduction primarily to manage AEs: 100% maintained MCyR; 100% maintained CCyR, and 79% maintained MMR. Conclusions: In Ph+ leukemia pts with the T315I mutation, where effective treatment options are limited, ponatinib continued to exhibit deep and durable responses with up to 6 years follow-up. Dose reductions to manage AEs did not impact maintenance of cytogenetic responses. The response rates and safety profile of T315I pts were comparable to, if not better than, those observed in the overall population of refractory CML and Ph+ ALL pts in ponatinib clinical trials. Disclosures Mauro:ARIAD Pharmaceuticals, Inc.: Consultancy. Cortes:ARIAD, BMS, Novartis, Pfizer, Teva: Consultancy, Research Funding. Hochhaus:ARIAD Pharmaceuticals, Inc.: Research Funding. Baccarani:ARIAD, Novartis, BMS: Consultancy; ARIAD, Novartis, BMS, Pfizer, Teva: Honoraria; ARIAD, Novartis, BMS, Pfizer, Teva: Speakers Bureau. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Guilhot:ARIAD Pharmaceuticals, Inc.: Honoraria. Deininger:BMS, Novartis, Celgene, Genzyme, Gilead: Research Funding; BMS, ARIAD, Novartis, Incyte, Pfizer: Advisory Board, Advisory Board Other; BMS, ARIAD, Novartis, Incyte, Pfizer: Consultancy. Kantarjian:ARIAD Pharmaceuticals, Inc., Pfizer, Amgen: Research Funding. Shah:ARIAD Pharmaceuticals, Inc., BMS: Research Funding. Flinn:ARIAD Pharmaceuticals, Inc.: Research Funding. Lustgarten:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Haluska:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Clackson:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Talpaz:ARIAD Pharmaceuticals, Inc., BMS, Sanofi, Incyte, Pfizer: Research Funding.

Long-term follow-up of phase II trial of docetaxel and cisplatin with concurrent thoracic radiation therapy for locally advanced non-small cell lung cancer

Background. Chemoradiation improves survival for patients with locally advanced non-small cell lung cancer (NSCLC), but clinical outcomes beyond five years are rarely reported. The aim of the present study was to identify the long-term results of a phase II study of docetaxel and cisplatin with concurrent thoracic radiation. Methods. We previously reported short-term outcomes from the phase II study, which enrolled 42 patients (aged ≤ 75 years) with unresectable stage III NSCLC. We continued to follow these patients for long-term clinical outcomes. Results. At a median follow-up for all patients of 6.3 years (range: 5.2–7.1 years), the median survival time was 2.1 years and the actual five-year survival rate was 31%. Among 14 patients who were progression-free longer than two years, three patients died due to bacterial or fungal pneumonia and one died due to gall bladder cancer. Conclusions. Thirty-one percent of locally advanced patients having NSCLC treated with docetaxel and cisplatin and concurrent thoracic radiation survived beyond five years. Progression-free patients might be cautiously followed up taking precautions against emerging pneumonia.

Long-term follow-up of phase III trial of docetaxel and cisplatin (DP) versus mitomycin, vindesine, and cisplatin (MVP) with concurrent thoracic radiation therapy (TRT) for locally advanced non-small cell lung cancer (OLCSG 0007).

7048 Background: Although overall survival (OS) and progression-free survival (PFS) tended to be longer in the DP arm than in the MVP arm, there was no significant difference in the first report (A...

Velcade (V)-Thalidomide (T)-Dexamethasone (D) for Advanced and Refractory Multiple Myeloma (MM): Long-Term Follow-Up of Phase I–II Trial UARK 2001-37: Superior Outcome in Patients with Normal Cytogenetics and No Prior T.

INTRODUCTION: A 2-arm Phase I/II trial was initiated to determine activity and toxicities of the VTD combination in patients with advanced and refractory MM.METHODOLOGY: Of 85 patients enrolled, 63 (74%) had abnormal cytogenetics (CA) including 40 patients with deletion of chromosome 13; 71 (84%) had received 1 prior autotransplant, including 56 (66%) with 2 prior autotransplants; 73% had previously received T; none had received prior V. V was given at a starting dose of 1.0 mg/m2 (group A) on days 1, 4, 8, and 11 every 21 days; T was added with the 2nd cycle at dose increments of 50, 100, 150, and 200 mg daily in cohorts of at least 10 patients. In the absence of grade > 2 peripheral neuropathy (PN) with V at 1.0 mg/m2 plus T 200mg, V was then increased to 1.3 mg/m2 (group B); T was added in the same incremental dosing schedule as in group A. D was added (20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 every 21 days) with cycle #4 if partial response (PR) or better was not achieved; 34 patients received D, 19 in group A and 15 in group B. PR was defined as ≥ 50% reduction in serum M-protein and/or ≥ 75% reduction of urine M-protein. Responses were computed on an intent-to-treat basis.RESULTS: Median numbers of cycles in group A were 6, 10, 7, 2 per T cohort and 12, 6, 11, 3, respectively, in group B. PR was obtained in 55% of patients, including 16% who achieved ≥ n-CR; an additional 15% had ≥ 25% M-protein reduction. Median EFS/OS for all 85 patients were 9/22 mos. Compared to group A, group B had a superior 12-mo EFS (47% vs. 26%) and OS (79% vs. 57%) (p=0.008/p=0.06); however, the 2 groups were not well balanced with regard to recognized prognostic factors (group A contained more patients with a low albumin level, high B2M, abnormal cytogenetics [CA] and high bone marrow plasmacytosis). No T dose effect on EFS or OS was apparent (≤ 100 mg/d, n=42; > 100 mg/d, n=43). Both EFS (p=0.01) and OS (p=0.03) were shorter in the presence of CA. EFS was also inferior in case of prior T (26% vs. 63%, p=0.03). The most common grade 3 or 4 toxicity was myelosuppression (thrombocytopenia and neutropenia). The proportion of patients in group A with PN grade > 1 was 41% at study entry and only slightly increased to 50% after cycle 5, with no T dose effect; the corresponding values for group B were 51% at study entry and 56% after cycle 5, with PN reaching grade 3 in 2/6 patients in the T=200 mg cohort. Syncope was observed in 2/6 patients receiving T=200mg in group B. Thus, in group A no T-MTD was reached, whereas it was 150mg in group B.CONCLUSION: VTD is well tolerated at V 1.0 + T 200mg and V 1.3 + T 150mg. Its overall remarkable activity in a high-risk patient population yielded superior EFS/OS in the absence of either CA or prior T. The imbalance of prognostically relevant features, however, precludes a final dose recommendation for V. VTD (V=1.0, T=200mg, D=40mg) has since been combined with PACE combination chemotherapy (VTD-PACE) in Total Therapy 3 (TT3), raising >=n-CR rates beyond 80% compared to 65% with TT2+T (ASCO 2005), permitting robust PBSC collection >20 million CD34 cells/kg in >90% of >150 patients enrolled, when performed after the first cycle of VDT-PACE.