Dataset Information

Efficacy and Safety of TRC105 Plus Pazopanib vs Pazopanib Alone for Treatment of Patients With Advanced Angiosarcoma: A Randomized Clinical Trial.

ABSTRACT:

Importance

Angiosarcoma is a rare sarcoma subtype with a poor outcome. Carotuximab plus pazopanib produced a median progression-free survival (PFS) of 7.8 months in pazopanib-naive patients with chemotherapy-refractory angiosarcoma in a phase 1/2 trial.

Objective

To determine whether carotuximab plus pazopanib improves PFS compared with pazopanib alone in patients with advanced angiosarcoma.

Design, setting, and participants

The TAPPAS Trial: An Adaptive Enrichment Phase 3 Trial of TRC105 and Pazopanib vs Pazopanib Alone in Patients With Advanced Angiosarcoma was a multinational, multicenter, open-label, parallel-group, phase 3 randomized clinical trial of 123 patients 18 years or older with advanced angiosarcoma that was conducted between February 16, 2017, and April 12, 2019, at 31 sites in the US and the European Union. Patients were randomized 1:1 to receive pazopanib alone or carotuximab plus pazopanib. The trial incorporated an adaptive enrichment design. Inclusion criteria were no more than 2 prior lines of systemic therapy and an Eastern Cooperative Oncology Group performance status of 0 or 1. The efficacy analysis used the intent-to-treat population; the safety analysis included all patients who received a dose of either study drug.

Exposures

Oral pazopanib, 800 mg/d, or intravenous carotuximab, 10 mg/kg, administered weekly, plus oral pazopanib, 800 mg/d, with dose modification allowed per patient tolerance or until disease progression.

Main outcomes and measures

The primary end point was PFS, assessed by blinded independent radiographic and cutaneous photographic review per Response Evaluation Criteria in Solid Tumors (RECIST) guidelines, version 1.1. Secondary end points included the objective response rate and overall survival. An interim analysis to determine the final sample size was conducted after enrollment of 123 patients. PFS in the group receiving pazopanib alone was compared with PFS in the group receiving carotuximab plus pazopanib using the log rank test.

Results

Of 114 patients with evaluable data (53 in the pazopanib arm and 61 in the carotuximab plus pazopanib arm), 69 (61%) were female and the median age was 68 years (range, 24-82 years); 57 (50%) had cutaneous disease and 32 (28%) had had no prior treatment. The primary end point (PFS) was not reached (hazard ratio [HR], 0.98; 95% CI, 0.52-1.84; P = .95), with a median of 4.3 months (95% CI, 2.9 months to not reached) for pazopanib and 4.2 months (95% CI, 2.8-8.3 months) for the combination arm. The most common all-grade adverse events in the single-agent pazopanib arm vs the combination arm were fatigue (29 patients [55%] vs 37 [61%]), headache (12 patients [23%] vs 39 [64%]), diarrhea (27 patients [51%] vs 35 [57%]), nausea (26 patients [49%] vs 29 [48%]), vomiting (12 patients [23%] vs 23 [38%]), anemia (5 patients [9%] vs 27 [44%]), epistaxis (2 patients [4%] vs 34 [56%]), and hypertension (29 patients [55%] vs 22 [36%]).

Conclusions and relevance

In this phase 3 randomized clinical trial, carotuximab plus pazopanib did not improve PFS compared with pazopanib alone in patients with advanced angiosarcoma.

Trial registration

ClinicalTrials.gov Identifier: NCT02979899.

SUBMITTER: Jones RL

PROVIDER: S-EPMC8972152 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Publications

Efficacy and Safety of TRC105 Plus Pazopanib vs Pazopanib Alone for Treatment of Patients With Advanced Angiosarcoma: A Randomized Clinical Trial.

Jones Robin L RL Ravi Vinod V Brohl Andrew S AS Chawla Sant S Ganjoo Kristen N KN Italiano Antoine A Attia Steven S Burgess Melissa A MA Thornton Katherine K Cranmer Lee D LD Cheang Maggie Chon U MCU Liu Lingyun L Robertson Liz L Adams Bonne B Theuer Charles C Maki Robert G RG

JAMA oncology 20220501 5

<h4>Importance</h4>Angiosarcoma is a rare sarcoma subtype with a poor outcome. Carotuximab plus pazopanib produced a median progression-free survival (PFS) of 7.8 months in pazopanib-naive patients with chemotherapy-refractory angiosarcoma in a phase 1/2 trial.<h4>Objective</h4>To determine whether carotuximab plus pazopanib improves PFS compared with pazopanib alone in patients with advanced angiosarcoma.<h4>Design, setting, and participants</h4>The TAPPAS Trial: An Adaptive Enrichment Phase 3 ...[more]

PMID: 35357396

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Project description:BackgroundMajor challenges in clinical trials of ultra-orphan oncology diseases include limited patient availability and paucity of reliable prior data for estimating the treatment effect and, therefore, determining optimal sample size. Angiosarcoma (AS), a particularly aggressive form of soft tissue sarcoma with an incidence of about 2000 cases per year in the United States and Europe is poorly addressed by current systemic therapies. Pazopanib, an inhibitor of vascular endothelial growth factor receptor (VEGFR) is approved for the treatment of AS, with modest benefit. TRC105 (carotuximab) is a monoclonal antibody to endoglin, an essential angiogenic target highly expressed on proliferating endothelium and both tumor vessels and tumor cells in AS, that has the potential to complement VEGFR tyrosine kinase inhibitors. In a phase I/II study of soft tissue sarcoma, TRC105 combined safely with pazopanib and the combination demonstrated durable complete responses and encouraging progression-free survival (PFS). In addition, there was a suggestion of superior benefit in patients with cutaneous lesions versus those with the non-cutaneous lesions.Patients and methodsThis article describes the design of a recently initiated phase III trial of TRC105 And Pazopanib versus Pazopanib alone in patients with advanced AngioSarcoma (TAPPAS trial). Given the ultra-orphan status of the disease and the paucity of reliable prior data on PFS or overall survival (end points required for regulatory approval as a pivotal trial), an adaptive design incorporating population enrichment and sample size re-estimation was implemented. The design incorporated regulatory input from the Food and Drug Administration (FDA) and European Medicines Agency and proceeded following special protocol assessment designation by the FDA.ConclusionsIt is shown that the benefit of the adaptive design as compared with a conventional single-look design arises from the learning and subsequent improvements in power that occur after an unblinded analysis of interim data.Registered on clinicaltrials.govNCT02979899.

Project description:ImportanceSafe and effective therapies for untreated, advanced gastric/gastroesophageal junction (G/GEJ) cancer remain an unmet need.ObjectiveTo evaluate the antitumor activity of pembrolizumab, pembrolizumab plus chemotherapy, or chemotherapy alone in patients with untreated, advanced G/GEJ cancer with programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or greater.Design, setting, and participantsThe phase 3 KEYNOTE-062 randomized, controlled, partially blinded interventional trial enrolled 763 patients with untreated, locally advanced/unresectable or metastatic G/GEJ cancer with PD-L1 CPS of 1 or greater from 200 centers in 29 countries between September 18, 2015, and May 26, 2017.InterventionsPatients were randomized 1:1:1 to pembrolizumab 200 mg, pembrolizumab plus chemotherapy (cisplatin 80 mg/m2/d on day 1 plus fluorouracil 800 mg/m2/d on days 1 to 5 or capecitabine 1000 mg/m2 twice daily), or chemotherapy plus placebo, every 3 weeks.Main outcomes and measuresPrimary end points were overall survival (OS) and progression-free survival (PFS) in patients with PD-L1 CPS of 1 or greater or 10 or greater.ResultsA total of 763 patients were randomized to pembrolizumab (n = 256), pembrolizumab plus chemotherapy (n = 257), or chemotherapy (n = 250). The median (range) age of all patients in the study cohort was 62 (20-87) years; 554 of 763 (72.6%) were men. At final analysis, after a median (range) follow-up of 29.4 (22.0-41.3) months, pembrolizumab was noninferior to chemotherapy for OS in patients with CPS of 1 or greater (median, 10.6 vs 11.1 months; hazard ratio [HR], 0.91; 99.2% CI, 0.69-1.18). Pembrolizumab monotherapy was not superior to chemotherapy in patients with CPS of 1 or greater. Pembrolizumab prolonged OS vs chemotherapy in patients with CPS of 10 or greater (median, 17.4 vs 10.8 months; HR, 0.69; 95% CI, 0.49-0.97), but this difference was not statistically tested. Pembrolizumab plus chemotherapy was not superior to chemotherapy for OS in patients with CPS of 1 or greater (12.5 vs 11.1 months; HR, 0.85; 95% CI, 0.70-1.03; P = .05) or CPS of 10 or greater (12.3 vs 10.8 months; HR, 0.85; 95% CI, 0.62-1.17; P = .16) or for PFS in patients with CPS of 1 or greater (6.9 vs 6.4 months; HR, 0.84; 95% CI, 0.70-1.02; P = .04). Grade 3 to 5 treatment-related adverse event rates for pembrolizumab, pembrolizumab plus chemotherapy, and chemotherapy were 17%, 73%, and 69%, respectively.Conclusions and relevanceThis phase 3 randomized clinical trial found that among patients with untreated, advanced G/GEJ cancer, pembrolizumab was noninferior to chemotherapy, with fewer adverse events observed. Pembrolizumab or pembrolizumab plus chemotherapy was not superior to chemotherapy for the OS and PFS end points tested.Trial registrationClinicalTrials.gov Identifier: NCT02494583.

Project description:ImportanceBecause of socioeconomic factors, many patients with advanced non-small cell lung cancer (NSCLC) do not receive immunotherapy in the first-line setting. It is unknown if the combination of immunotherapy with chemotherapy can provide clinical benefits in immunotherapy-naive patients with disease progression after treatment with platinum-based chemotherapy.ObjectiveTo evaluate the safety and efficacy of the combination of pembrolizumab plus docetaxel in patients with previously treated advanced NSCLC following platinum-based chemotherapy regardless of EGFR variants or programmed cell death ligand 1 status.Design, setting, and participantsThe Pembrolizumab Plus Docetaxel for Advanced Non-Small Cell Lung Cancer (PROLUNG) trial randomized 78 patients with histologically confirmed advanced NSCLC in a 1:1 ratio to receive either pembrolizumab plus docetaxel or docetaxel alone from December 2016 through May 2019.InterventionsThe experimental arm received docetaxel on day 1 (75 mg/m2) plus pembrolizumab on day 8 (200 mg) every 3 weeks for up to 6 cycles followed by pembrolizumab maintenance until progression or unacceptable toxic effects. The control arm received docetaxel monotherapy.Main outcomes and measuresThe primary end point was overall response rate (ORR). Secondary end points included progression-free survival (PFS), overall survival, and safety.ResultsAmong 78 recruited patients, 32 (41%) were men, 34 (44%) were never smokers, and 25 (32%) had an EGFR/ALK alteration. Forty patients were allocated to receive pembrolizumab plus docetaxel, and 38 were allocated to receive docetaxel. A statistically significant difference in ORR, assessed by an independent reviewer, was found in patients receiving pembrolizumab plus docetaxel vs patients receiving docetaxel (42.5% vs 15.8%; odds ratio, 3.94; 95% CI, 1.34-11.54; P = .01). Patients without EGFR variations had a considerable difference in ORR of 35.7% vs 12.0% (P = .06), whereas patients with EGFR variations had an ORR of 58.3% vs 23.1% (P = .14). Overall, PFS was longer in patients who received pembrolizumab plus docetaxel (9.5 months; 95% CI, 4.2-not reached) than in patients who received docetaxel (3.9 months; 95% CI, 3.2-5.7) (hazard ratio, 0.24; 95% CI, 0.13-0.46; P < .001). For patients without variations, PFS was 9.5 months (95% CI, 3.9-not reached) vs 4.1 months (95% CI, 3.5-5.3) (P < .001), whereas in patients with EGFR variations, PFS was 6.8 months (95% CI, 6.2-not reached) vs 3.5 months (95% CI, 2.3-6.2) (P = .04). In terms of safety, 23% (9 of 40) vs 5% (2 of 38) of patients experienced grade 1 to 2 pneumonitis in the pembrolizumab plus docetaxel and docetaxel arms, respectively (P = .03), while 28% (11 of 40) vs 3% (1 of 38) experienced any-grade hypothyroidism (P = .002). No new safety signals were identified.Conclusions and relevanceIn this phase 2 study, the combination of pembrolizumab plus docetaxel was well tolerated and substantially improved ORR and PFS in patients with advanced NSCLC who had previous progression after platinum-based chemotherapy, including NSCLC with EGFR variations.Trial registrationClinicalTrials.gov Identifier: NCT02574598.

Project description:ImportanceDysregulated metabolism is a hallmark of renal cell carcinoma (RCC). Glutaminase is a key enzyme that fuels tumor growth by converting glutamine to glutamate. Telaglenastat is an investigational, first-in-class, selective, oral glutaminase inhibitor that blocks glutamine utilization and downstream pathways. Preclinically, telaglenastat synergized with cabozantinib, a VEGFR2/MET/AXL inhibitor, in RCC models.ObjectiveTo compare the efficacy and safety of telaglenastat plus cabozantinib (Tela + Cabo) vs placebo plus cabozantinib (Pbo + Cabo).Design, setting, and participantsCANTATA was a randomized, placebo-controlled, double-blind, pivotal trial conducted at sites in the US, Europe, Australia, and New Zealand. Eligible patients had metastatic clear-cell RCC following progression on 1 to 2 prior lines of therapy, including 1 or more antiangiogenic therapies or nivolumab plus ipilimumab. The data cutoff date was August 31, 2020. Data analysis was performed from December 2020 to February 2021.InterventionsPatients were randomized 1:1 to receive oral cabozantinib (60 mg daily) with either telaglenastat (800 mg twice daily) or placebo until disease progression or unacceptable toxicity.Main outcomes and measuresThe primary end point was progression-free survival (Response Evaluation Criteria in Solid Tumors version 1.1) assessed by blinded independent radiology review.ResultsA total of 444 patients were randomized: 221 to Tela + Cabo (median [range] age, 61 [21-81] years; 47 [21%] women and 174 [79%] men) and 223 to Pbo + Cabo (median [range] age, 62 [29-83] years; 68 [30%] women and 155 [70%] men). A total of 276 (62%) patients had received prior immune checkpoint inhibitors, including 128 with prior nivolumab plus ipilimumab, 93 of whom had not received prior antiangiogenic therapy. Median progression-free survival was 9.2 months for Tela + Cabo vs 9.3 months for Pbo + Cabo (HR, 0.94; 95% CI, 0.74-1.21; P = .65). Overall response rates were 31% (69 of 221) with Tela + Cabo vs 28% (62 of 223) with Pbo + Cabo. Treatment-emergent adverse event (TEAE) rates were similar between arms. Grade 3 to 4 TEAEs occurred in 160 patients (71%) with Tela + Cabo and 172 patients (79%) with Pbo + Cabo and included hypertension (38 patients [17%] vs 40 patients [18%]) and diarrhea (34 patients [15%] vs 29 patients [13%]). Cabozantinib was discontinued due to AEs in 23 patients (10%) receiving Tela + Cabo and 33 patients (15%) receiving Pbo + Cabo.Conclusions and relevanceIn this randomized clinical trial, telaglenastat did not improve the efficacy of cabozantinib in metastatic RCC. Tela + Cabo was well tolerated with AEs consistent with the known risks of both agents.Trial registrationClinicalTrials.gov Identifier: NCT03428217.

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Dataset Information

Efficacy and Safety of TRC105 Plus Pazopanib vs Pazopanib Alone for Treatment of Patients With Advanced Angiosarcoma: A Randomized Clinical Trial.

Importance

Objective

Design, setting, and participants

Exposures

Main outcomes and measures

Results

Conclusions and relevance

Trial registration

Publications

Efficacy and Safety of TRC105 Plus Pazopanib vs Pazopanib Alone for Treatment of Patients With Advanced Angiosarcoma: A Randomized Clinical Trial.

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