ESMO Magnitude of Clinical Benefit Scale (MCBS): An evaluation of systemic treatment trials for soft tissue sarcomas (STS).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 11553-11553
Author(s):  
Abdulazeez Salawu ◽  
Christopher Lemieux ◽  
Albiruni Ryan Abdul Razak
Keyword(s):  
Phase Ii ◽  
Clinical Benefit ◽  
Drug Class ◽  
Systemic Treatment ◽  
Objective Response ◽  
Soft Tissue Sarcomas ◽  
Phase Iii ◽  
Phase Ii Trials ◽  
Treatment Trials ◽  
Metastatic Setting

11553 Background: Patients with STS have poor prognosis in the metastatic setting. Although some treatment options are associated with improved outcomes, such as progression-free (PFS) or overall survival (OS), the overall magnitude of clinical benefit can be unclear. The ESMO MCBS is a validated and reproducible tool developed to quantify the clinical benefit of treatments evaluated in trials ( www.esmo.org/guidelines/esmo-mcbs ). Herein, we report the application of ESMO MCBS to systemic treatment trials involving metastatic STS patients. Methods: A systematic search of Medline, Embase and Cochrane databases for adult phase II and III trials in advanced STS (01/1998 to 12/2020) was carried out. Gastrointestinal stromal tumor trials were excluded. Outcomes, including but not limited to OS, PFS, objective response rate (ORR), toxicity and quality of life (QoL) data were extracted and analyzed. Studies with outcomes that met the criteria for ESMO MCBS v1.1 were evaluated to generate a score of 1 to 5 (score of ≥ 4: substantial benefit). MCBS scoring of each study was performed by at least 2 co-authors for consensus. Results: Among 3454 abstracts screened, a total of 140 Phase II and 28 phase IIII trials were identified. A total of 41 studies fulfilled the criteria for ESMO MCBS scoring. These include 5 phase III studies, as well as 9 randomized and 27 single-arm phase II trials. Fifteen studies involved specific histology, while remaining 26 studies were of all STS subtypes. Chemotherapy, alone or in combination was evaluated in 29 trials, while molecular-targeted agents (MTA) and immune checkpoint inhibitors (IO) were evaluated in 11 and 3 studies, respectively (Table). The median MCBS score was 2 (range 1-4), regardless of drug class or combination. Only 3 studies, all randomized in design, had a MCBS score of 4. All three trials were in the 2nd line setting or beyond, where there is no standard control treatment. None of the trials, irrespective of drug class had a score of 5 and no study showed evidence of significant improvement in QoL. The observed MCBS scores were low, partly because the trials evaluated mainly comprise single-arm studies without QoL assessments, restricting to a maximum MCBS score of 3. Conclusions: Most systemic therapy trials in advanced STS did not confer substantial clinical benefit when evaluated using MCBS. Although randomized phase 3 trials remain the gold standard of treatment evaluation, clinical benefit evaluation of STS trials using tools such as MCBS may be useful. Incorporation of QoL evaluation, even in single-arm studies should be prioritized in metastatic STS trials.[Table: see text]

“Getting to go” for FDA Approvals for the Treatment of Hematologic Versus Solid Tumor Malignancies: A Report from the Research on Adverse Drug Events and Reports (RADAR) Project

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2402-2402
Author(s):  
Elizabeth A Richey ◽  
Veena Shankaran ◽  
Steven Hirschfeld ◽  
Steven M Trifilio ◽  
June McKoy ◽  
...  
Keyword(s):  
Phase Ii ◽  
Solid Tumor ◽  
Clinical Benefit ◽  
Hematologic Malignancy ◽  
Hematologic Malignancies ◽  
Black Box ◽  
Phase Iii ◽  
Phase Ii Trials ◽  
Development Times ◽  
Black Box Warnings

Abstract Background: The accelerated approval (AA) regulation (21CFR314.510 Subpart H) is granted by the Food and Drug Administration (FDA) when drugs for serious medical illnesses are shown to be an improvement over available therapy. AA provides an option to use surrogate outcomes considered likely to predict clinical benefit. AA was initially developed to hasten access to HIV drugs, then, in 1995, AA was extended to cancer indications. Sponsors receiving AA are required to confirm clinical benefit (termed subpart H trials). Policy makers have several raised concerns: AA is no longer relevant today as the approval bar via this mechanism has been raised too high; many drugs that received AA did not complete subpart H trials; and some drugs approved by AA were subsequently found to be unsafe or ineffective. Methods: Using publicly available databases, we compared safety, efficacy, clinical development times, and subpart H completion rates for FDA-approved new molecular entities (NMEs) for hematologic and solid tumor cancers from 1995–2008. Results: 37% of all oncology NMEs received AA versus regular approval (64% during 1995–2003 and 33% during 2004–2008). Twenty oncology NMEs received FDA approval for hematologic malignancies (lymphomas, leukemias, Kaposi’s sarcoma, and myelodysplastic syndromes), accounting for 34% of regular approvals and 53% of AAs for oncology NMEs. Compared to NMEs approved for solid tumors, NMEs approved for hematologic malignancies were more likely to involve Orphan Drug indications (95% vs. 32%); to have shorter development times, defined as the interval between investigational new drug filing and marketing approval, (median 5.6 vs. 7.8 years); and to be approved based on phase II studies (65% vs. 29%). Prior to 2004, development times were similar for solid tumor and hematologic malignancy NMEs. Since 2004, development times have decreased by more than 2 years for hematologic malignancy NMEs, but not for solid tumor NMEs. 50% of NMEs approved for hematologic malignancies versus 71% of NMEs for solid tumor diagnoses are included in first-line cancer regimens in current National Comprehensive Cancer Network guidelines. Drugs approved for solid tumor and hematologic indications have similar safety profiles and efficacy; respectively, 30% and 38% carried black box warnings at initial approval, and 15% and 10% had black box warnings added post-approval. Studies confirming efficacy were completed for 89% of NMEs receiving AA for solid tumor indications versus 30% for NMEs receiving AA for hematologic malignancy indications. Concern that sponsors are not completing subpart H commitments has led the FDA to move from basing AA on final results of single-arm phase II trials to interim results of phase III trials. Conclusions: AAs for hematologic malignancy indications are less likely to complete Subpart H commitments. In the current era, development times for NMEs are shorter for hematologic malignancy versus solid tumor indications, principally related to the approval based on Phase II versus Phase III studies. Establishing a global policy that AA approval for cancer drugs should be based on interim results of phase III analyses rather than on final analyses of phase II trials may hamper development of novel therapies for hematologic malignancies. Solide tumor indications Hematologic malignancy indications 1995–2003 (n=21) 2004–2008 (n=10) 1995–2003 (n=11) 2004–2008 (n=9) Drugs receivving AA (%) 29 30 64 33 Orphan drugs (%) 24 40 100 78 Of AAs, Subpart H completion (%) 100 66 27 0 Approval based on phase II trial (%) 33 0 73 78 Median development time (years) 8.4 7.8 8.8 5.2

A randomized phase II trial of cabozantinib combined with PD-1 and CTLA-4 inhibition in metastatic soft tissue sarcoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS11583-TPS11583
Author(s):  
Vanessa Anne Eulo ◽  
Breelyn A. Wilky ◽  
Jingqin Luo ◽  
Angela C. Hirbe ◽  
Mia C. Weiss ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Soft Tissue ◽  
Phase Ii ◽  
Immune Checkpoint ◽  
Response Rate ◽  
Single Agent ◽  
Objective Response ◽  
Soft Tissue Sarcomas ◽  
Randomized Phase Ii ◽  
Metastatic Setting

TPS11583 Background: Soft tissue sarcomas (STS) are rare malignancies with poor prognosis in the metastatic setting. Current standard therapy includes anthracycline based chemotherapy. Cabozantinib is a multikinase inhibitor that has demonstrated efficacy in solid tumors such as renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC). A phase II study of cabozantinib in advanced STS is underway. Cabozantinib in combination with immune checkpoint blockade has shown clinical benefit in several tumor types including HCC, RCC, non-small cell lung cancer, and urothelial carcinoma. Since cabozantinib may alter PD-1 expression in regulatory T-cells and promote an immune permissive environment, we hypothesize that combining cabozantinib with immune checkpoint inhibition is a therapeutic strategy that will be more effective than cabozantinib alone. Additionally, the design of the trial will allow assessment of whether pretreatment with cabozantinib will enhance the efficacy of nivolumab and ipilimumab alone. Methods: This is an open label, multicenter, randomized phase II clinical trial of cabozantinib (60mg orally daily as a single agent, 40mg in combination) with or without combination Ipilimumab (ipi, 1mg/kg IV every 3 weeks for 4 doses) and Nivolumab (nivo, 3mg/kg IV every 3 weeks for four doses, then 480mg IV every 4 weeks) in patients (pts) with unresectable or metastatic STS refractory to up to two lines of chemotherapy. 105 pts with non-translocation driven sarcomas will be enrolled at three US sites and randomized 2:1 to the combination group. Pts will be stratified by prior pazopanib use and balanced for histologies. Patients who progress on arm A will cross over to combination therapy (arm B). The primary efficacy endpoint is objective response rate (ORR) by RECIST 1.1. 35 patients in Cohort A (cabozantinib alone) and 70 patients in Cohort B (cabozantinib plus ipi/nivo) will be required to detect an increase of the ORR from 10% in cohort A to 30% in cohort B with 81% power with a one-sided alpha level of 10%. Key eligibility criteria include: at least 18 years of age, ECOG performance status of 0 or 1, ≤2 prior lines of therapy and measurable disease. Exclusion criteria include: translocation-driven sarcoma except alveolar soft part sarcoma (ASPS), prior immunotherapy, and chronic use of corticosteroids or other immunosuppression. Secondary endpoints are safety, overall and progression free survival, disease control rate, and response rate to ipilimumab and nivolumab after cabozantinib pretreatment. Mandatory tumor biopsies pre-treatment and at 6 weeks will be obtained. Peripheral blood will be collected for circulating immune phenotyping. Enrollment will occur at 3 participating institutions and is expected to be completed in 2022. Clinical trial information: NCT04551430.

A phase II clinical trial of neoadjuvant trabectedin in patients with nonmetastatic advanced myxoid/round cell liposarcoma (MRCL)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 10525-10525
Author(s):  
A. Gronchi ◽  
A. Le Cesne ◽  
N. B. Bui ◽  
E. Palmerini ◽  
G. Demetri ◽  
...  
Keyword(s):  
Phase Ii ◽  
Response Rate ◽  
Objective Response ◽  
Locally Advanced ◽  
Soft Tissue Sarcomas ◽  
Pathological Response ◽  
Phase Iii ◽  
Significant Activity ◽  
Tumor Mass ◽  
Preliminary Results

10525 Background: Trabectedin (ET-743, Yondelis), a marine-derived alkaloid has demonstrated significant activity in the treatment of soft tissue sarcomas (STS) in phase III trials, and has recently received EMEA approval in this indication. A subtype that accounts for 10% of STS, MRCL, displays the fusion FUS-CHOP in 95% of all cases. Preliminary results of neoadjuvant trabectedin (T) in advanced MRCL show reduction in the radiological density of the tumor, clinical improvement, and a pathological complete response (pCR) in the resected tumor mass. A phase II study to further determine the response to T in the MRCL population is presented. Methods: In this multicenter Phase II trial, patients (pts) with locally advanced (stage III) or locally recurrent MRCL were treated for 3 - 6 cycles with T (1.5 mg/m2 q3wk) in the neoadjuvant setting. Main endpoints were: pCR rate, objective response rate by RECIST, and correlation of molecular parameters from tissue samples with clinical outcomes. Results: Twenty-five pts with locally advanced MRCL have been recruited, of whom 20 are evaluable. All had the translocation (t12q13, 16p11) which causes the chimeric FUS-CHOP. Median age was 53 (23–75) and male:female ratio was 1. Thirteen pts completed therapy and underwent curative surgery. Pathological assessment was performed in 10 pts: 2 achieved pCR, 1 as per central pathology review and 1 by local pathology assessment. In addition, 1 pt had a very good pathological response. Ten patients remain to be histologically evaluated. Response rate by RECIST from pts who completed therapy was: 6 partial responses (46%) and 7 disease stabilizations. Remarkably, pathological response does not entirely correlate with response by RECIST since the pts with pCR still had radiological disease but no malignant component was found in the excised tumor mass (only connective and reactive tissue). Two serious adverse reactions of severe rhabdomyolysis, and asthenia, nausea and transaminase elevation were reported. Most common toxicities were liver enzyme elevation, neutropenia and thrombocytopenia. Conclusions: These preliminary results in terms of objective and complete pathologic responses, strongly suggest that T may have a role in the neoadjuvant setting in pts with MRCL. [Table: see text]

Ipilimumab (Ipi) retreatment at 10 mg/kg in patients with metastatic melanoma previously treated in phase II trials.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 9059-9059 ◽  
Author(s):  
Bart Neyns ◽  
Jeffrey S. Weber ◽  
Celeste Lebbé ◽  
Michele Maio ◽  
Kaan Harmankaya ◽  
...  
Keyword(s):  
Phase Ii ◽  
Safety Profile ◽  
Human Monoclonal Antibody ◽  
Objective Response ◽  
Primary Objective ◽  
Small Sample ◽  
Phase Iii ◽  
Phase Ii Trials ◽  
Study Results

9059 Background: Ipi is a fully human monoclonal antibody that binds to cytotoxic T-lymphocyte antigen-4 to augment antitumor immune responses. In phase III study MDX010-20, where patients (pts) could be retreated if they met safety criteria and achieved an objective response or stable disease ≥3 months from the end of the induction period (q3 weeks for 4 doses), 21 of 31 pts (68%) retreated with Ipi reestablished disease control. CA184-025 is a roll-over study of extended Ipi treatment or survival follow-up in pts who received Ipi in phase II trials, with the primary objective of evaluating safety during extended treatment. We report the safety profile in pts retreated with Ipi in study 025. Methods: Eligible pts in phase II trials CA184-004, -007, -008, -022, MDX010-08, or -015 were enrolled in study 025 (N=248) to receive retreatment (at the time of progression), extended maintenance (if no prior progression), or survival follow-up only. Pts were ineligible for retreatment if they had experienced a grade 3-4 non-skin toxicity during prior Ipi therapy. Ipi was administered at 10 mg/kg, q3 weeks for 4 doses, to 111 pts who initially received Ipi induction at 0.3, 3, or 10 mg/kg in a parent study. Results: In this selected population of eligible pts, the nature and frequency of immune-related adverse events (irAEs) during retreatment were similar to those reported in previous studies, which most commonly affected the GI tract and skin (Table). There were no new types of drug-related irAEs and no grade 5 irAEs upon retreatment. Conclusions: Retreatment with Ipi at 10 mg/kg in these pts was generally well tolerated and the safety profile was similar to that during induction dosing in the parent studies. The higher frequencies of irAEs at lower doses should be interpreted with caution given the small sample sizes. An ongoing, randomized phase II trial will evaluate the clinical benefit of Ipi retreatment. Clinical trial information: NCT00162123. [Table: see text]

Activity of cabazitaxel in patients with metastatic or inoperable locally advanced dedifferentiated liposarcoma: European Organization for Research and Treatment of Cancer (EORTC) Phase II trial 1202.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 11556-11556
Author(s):  
Roberta Sanfilippo ◽  
Richard L Hayward ◽  
Jammbe Musoro ◽  
Charlotte Benson ◽  
Michael Gordon Leahy ◽  
...  
Keyword(s):  
Phase Ii ◽  
Primary Endpoint ◽  
Phase Ii Trial ◽  
Objective Response ◽  
Locally Advanced ◽  
Soft Tissue Sarcomas ◽  
Phase Iii ◽  
European Organization ◽  
Drug Clinical Trial ◽  
Stage 1

11556 Background: The optimal treatment for patients with advanced dedifferentiated (DD) liposarcoma (LPS) remains uncertain. Single agents which are most effective include doxorubicin and ifosfamide but, as with soft tissue sarcomas (STS) in general, objective response rates (ORR) and progression free survival (PFS) are very modest. Cabazitaxel exerts its effect through inhibition of microtubular disassembly and has been shown to be relatively safe, effective and well-tolerated. EORTC 1202 assessed whether cabazitaxel demonstrated sufficient antitumor activity in patients with metastatic or inoperable locally advanced DD LPS to justify further investigation in a phase III setting. Methods: This was an international multi-center, open label single arm phase II trial. Eligible patients with metastatic or inoperable locally advanced DD LPS were treated with cabazitaxel 25mg/m² IV infusion over 1 hour every 21 days. Primary endpoint was PFS rate at 12 weeks assessed by local investigator per RECIST 1.1. Based on a Simon two-stage design, at least 4 out of 17 (Stage 1) and 11 out of 37 (Stage 2) eligible and evaluable patients who are progression-free at 12 weeks were needed. Results: Forty patients were registered by 10 institutions in 4 countries between March 2015 and March 2019, with 2 patients being ineligible. Among the 38 eligible patients who started treatment, 3 (7.5 %) were still on treatment at the time of analysis. The number of cycles ranged from 1 to 30, with a median of 5; 26 patients (65%) received at least 4 cycles of cabazitaxel. Among the first 17 (Stage 1) and 37 (Stage 2), 11 and 20 patients were progression-free at 12 weeks respectively, satisfying the study decision rules. The PFS rate at 12 weeks for all 38 eligible patients was 52.6% (conditional 1-sided 95 % CI 38.3 – 100). Two patients (5.3%) achieved a confirmed partial response (PR) and 23 stable disease (SD) (60.5%). Disease control (PR+SD) was achieved in 25 patients (65.8%). Median PFS was 7.4 months (95%CI 2.8-10.3). The most common cabazitaxel -related grade >3 adverse events in all 40 registered patients were neutropenia (60%), febrile neutropenia (25%), fatigue (12.5%), and anemia (10%). There were no cabazitaxel-related deaths. Conclusions: EORTC 1202 met its primary endpoint, with 20/37 pts (54%) being progression-free at 12 weeks. Results of this trial confirm activity of cabazitaxel in patients with metastatic or inoperable locally advanced DD LPS and warrant further exploration of the drug. Clinical trial information: NCT01913652 .

Review of Phase II Trial Designs Used in Studies of Molecular Targeted Agents: Outcomes and Predictors of Success in Phase III

2008 ◽  
Vol 26 (8) ◽  
pp. 1346-1354 ◽  
Author(s):  
Robert H. El-Maraghi ◽  
Elizabeth A. Eisenhauer
Keyword(s):  
Phase Ii ◽  
Single Agent ◽  
Objective Response ◽  
Response Rates ◽  
Regulatory Approval ◽  
Phase Iii ◽  
Targeted Agents ◽  
Phase Ii Trials ◽  
End Points ◽  
End Point

Purpose Because the appropriate design and end points for phase II evaluation of targeted anticancer agents are unclear, we undertook a review of recent reports of phase II trials of targeted agents to determine the types of designs used, the planned end points, the outcomes, and the relationship between trial outcomes and regulatory approval. Methods We retrieved reports of single-agent phase II trials in six solid tumors for 19 targeted drugs. For each, we abstracted data regarding planned design and actual results. Response rates were examined for any relationship to eventual success of the agents, as determined by US Food and Drug Administration approval for at least one indication. Results Eighty-nine trials were identified. Objective response was the primary or coprimary end point in the majority of trials (61 of 89 trials). Fourteen reports were of randomized studies generally evaluating different doses of agents, not as controlled experiments. Enrichment for target expression was uncommon. Objective responses were seen in 38 trials; in 19 trials, response rates were more than 10%, and in eight, they were more than 20%. Agents with high response rates tended to have high nonprogression rates; renal cell carcinoma was the exception to this. Higher overall response rates were predictive of regulatory approval in the tumor types reviewed (P = .005). Conclusion In practice, phase II design for targeted agents is similar to that for cytotoxics. Objective response seems to be a useful end point for screening new targeted agents because, in our review, its observation predicted for eventual success. Improvements in design are recommended, as is more frequent inclusion of biological questions as part of phase II trials.

scholarly journals Unconventional Anticancer Agents: A Systematic Review of Clinical Trials

2006 ◽  
Vol 24 (1) ◽  
pp. 136-140 ◽  
Author(s):  
Andrew J. Vickers ◽  
Joyce Kuo ◽  
Barrie R. Cassileth
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Cancer Patients ◽  
Phase Ii ◽  
Dose Finding ◽  
Phase Iii ◽  
High Dose ◽  
Free Text ◽  
Phase Ii Trials ◽  
Off Label

Purpose A substantial number of cancer patients turn to treatments other than those recommended by mainstream oncologists in an effort to sustain tumor remission or halt the spread of cancer. These unconventional approaches include botanicals, high-dose nutritional supplementation, off-label pharmaceuticals, and animal products. The objective of this study was to review systematically the methodologies applied in clinical trials of unconventional treatments specifically for cancer. Methods MEDLINE 1966 to 2005 was searched using approximately 200 different medical subject heading terms (eg, alternative medicine) and free text words (eg, laetrile). We sought prospective clinical trials of unconventional treatments in cancer patients, excluding studies with only symptom control or nonclinical (eg, immune) end points. Trial data were extracted by two reviewers using a standardized protocol. Results We identified 14,735 articles, of which 214, describing 198 different clinical trials, were included. Twenty trials were phase I, three were phase I and II, 70 were phase II, and 105 were phase III. Approximately half of the trials investigated fungal products, 20% investigated other botanicals, 10% investigated vitamins and supplements, and 10% investigated off-label pharmaceuticals. Only eight of the phase I trials were dose-finding trials, and a mere 20% of phase II trials reported a statistical design. Of the 27 different agents tested in phase III, only one agent had a prior dose-finding trial, and only for three agents was the definitive study initiated after the publication of phase II data. Conclusion Unconventional cancer treatments have not been subject to appropriate early-phase trial development. Future research on unconventional therapies should involve dose-finding and phase II studies to determine the suitability of definitive trials.

Design Issues of Randomized Phase II Trials and a Proposal for Phase II Screening Trials

2005 ◽  
Vol 23 (28) ◽  
pp. 7199-7206 ◽  
Author(s):  
Lawrence V. Rubinstein ◽  
Edward L. Korn ◽  
Boris Freidlin ◽  
Sally Hunsberger ◽  
S. Percy Ivy ◽  
...  
Keyword(s):  
Phase Ii ◽  
False Positive ◽  
Standard Treatment ◽  
False Negative ◽  
Error Rates ◽  
Targeted Treatment ◽  
Phase Iii ◽  
Phase Ii Trials ◽  
Treatment Control ◽  
Randomized Phase Ii

Future progress in improving cancer therapy can be expedited by better prioritization of new treatments for phase III evaluation. Historically, phase II trials have been key components in the prioritization process. There has been a long-standing interest in using phase II trials with randomization against a standard-treatment control arm or an additional experimental arm to provide greater assurance than afforded by comparison to historic controls that the new agent or regimen is promising and warrants further evaluation. Relevant trial designs that have been developed and utilized include phase II selection designs, randomized phase II designs that include a reference standard-treatment control arm, and phase II/III designs. We present our own explorations into the possibilities of developing “phase II screening trials,” in which preliminary and nondefinitive randomized comparisons of experimental regimens to standard treatments are made (preferably using an intermediate end point) by carefully adjusting the false-positive error rates (α or type I error) and false-negative error rates (β or type II error), so that the targeted treatment benefit may be appropriate while the sample size remains restricted. If the ability to conduct a definitive phase III trial can be protected, and if investigators feel that by judicious choice of false-positive probability and false-negative probability and magnitude of targeted treatment effect they can appropriately balance the conflicting demands of screening out useless regimens versus reliably detecting useful ones, the phase II screening trial design may be appropriate to apply.

scholarly journals Trends in Phase II Trials for Cancer Therapies

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 178
Author(s):  
Faruque Azam ◽  
Alexei Vazquez
Keyword(s):  
Phase Ii ◽  
Null Model ◽  
Surrogate Endpoint ◽  
Response Rates ◽  
Drug Combinations ◽  
Phase Iii ◽  
Cancer Drug ◽  
Cancer Therapies ◽  
Targeted Agents ◽  
Phase Ii Trials

Background: Drug combinations are the standard of care in cancer treatment. Identifying effective cancer drug combinations has become more challenging because of the increasing number of drugs. However, a substantial number of cancer drugs stumble at Phase III clinical trials despite exhibiting favourable efficacy in the earlier Phase. Methods: We analysed recent Phase II cancer trials comprising 2165 response rates to uncover trends in cancer therapies and used a null model of non-interacting agents to infer synergistic and antagonistic drug combinations. We compared our latest efficacy dataset with a previous dataset to assess the progress of cancer therapy. Results: Targeted therapies reach higher response rates when used in combination with cytotoxic drugs. We identify four synergistic and 10 antagonistic combinations based on the observed and expected response rates. We demonstrate that recent targeted agents have not significantly increased the response rates. Conclusions: We conclude that either we are not making progress or response rate measured by tumour shrinkage is not a reliable surrogate endpoint for the targeted agents.

A phase II trial combining tumor-targeting TP53 gene therapy with gemcitabine/nab-paclitaxel as a second-line treatment for metastatic pancreatic cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4139-4139
Author(s):  
Chris Poki Leung ◽  
Minal A. Barve ◽  
Ming-Shiang Wu ◽  
Kathleen F. Pirollo ◽  
James F. Strauss ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Objective Response ◽  
Tp53 Gene ◽  
Phase Iii ◽  
Published Data ◽  
Line Treatment ◽  
Second Line ◽  
First Line

4139 Background: Nearly all stage IV pancreatic adenocarcinoma (PAC) patients progress after first-line treatment, and second-line options are limited. SGT-53 is an investigational product for tumor-targeted TP53 gene therapy that has completed phase Ia/Ib trials [Senser et al (2013), Mol Ther 21:1096; Pirollo et al (2016) Mol Ther 24:1697]. Methods: Here we provide an interim analysis of a Phase II trial (SGT53-02-1; NCT02340117) combining SGT-53 with gemcitabine/nab-paclitaxel (GEM/ABX). Eligible were first-line patients or those who had progressed after FOLFIRINOX (FFX) and/or gemcitabine-based therapy (second-line). In a 7-week treatment cycle, SGT-53 (3.6 mg DNA) was given once or twice weekly with GEM/ABX (1000 mg/m2/wk and 125 mg/m2/wk, respectively, for 3 of 4 weeks). Progression-free survival (PFS) and objective response rate (ORR) are primary endpoints.Overall survival (OS) and PFS are estimated by Kaplan-Meier analysis. Results: Of all evaluable patients (n=20), best response in 7 patients was determined to be partial response (PR) and 13 had stable disease (SD); none had progressive disease. In the second-line patients (n=11) there were 5 PR and 6 SD after 9 had failed FFX treatment, 3 had failed gemcitabine-based treatment and 1 had failed both. For patients with elevated CA19-9, SGT-53 + GEM/ABX resulted in marked reductions in the tumor marker. Published data for patients with PAC after therapy failure [Mita et al (2019) J Clin Med 8: 761; Portal et al (2015) Br J Cancer 113:989; Wang-Gillam et al (2016) Lancet 387:545] are shown for comparison. Notably, mPFS in our second-line patients was 7.4 months versus 3.1 months for the approved second-line therapy [Wang-Gillam et al (2016)]. This improvement in PFS exceeds the benchmark proposed to predict a clinically meaningful Phase III trial [Rahib et al (2016) Lancet Oncol 2:1209]. Conclusions: Our data suggest a clinically meaningful benefit of adding SGT-53 to GEM/ABX particularly for second-line PAC patients, most of whom had failed prior FFX treatment. Clinical trial information: NCT02340117. [Table: see text]

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