Phase IB/II Randomized Study of FOLFIRINOX Plus Pegylated Recombinant Human Hyaluronidase Versus FOLFIRINOX Alone in Patients With Metastatic Pancreatic Adenocarcinoma: SWOG S1313

PURPOSE Pegylated recombinant human hyaluronidase (PEGPH20) degrades hyaluronan (HA) and, in combination with chemotherapy, prolongs survival in preclinical models. The activity of PEGPH20 with modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX) was evaluated in patients with metastatic pancreatic cancer (mPC). MATERIALS AND METHODS Patients had untreated mPC, a performance status of 0 to 1, and adequate organ function. Tumor HA status was not required for eligibility. After a phase Ib dose-finding study of mFOLFIRINOX plus PEGPH20, the phase II open-label study randomly assigned patients (1:1) to the combination arm or to mFOLFIRINOX alone (n = 138). The primary end point was overall survival (OS). RESULTS PEGPH20 dosages of 3 µg/kg every 2 weeks were more tolerable than twice-weekly dosages used in the phase I study, so 3 µg/kg every 2 weeks was the phase II dosage. An amendment instituted enoxaparin prophylaxis in the PEGPH20 combination arm as a result of increased thromboembolic (TE) events. The planned interim futility analysis when 35 deaths (of 103 analyzable patients) occurred resulted in an OS hazard ratio (HR) of 2.07 that favored the control arm, and the study was closed to accrual. The treatment-related grade 3 to 4 toxicity was significantly increased in the PEGPH20 combination arm relative to control (odds ratio, 2.7; 95% CI, 1.1 to 7.1). The median OS in the mFOLFIRINOX arm was 14.4 months (95% CI, 10.1 to 15.7 months) versus 7.7 months (95% CI, 4.6 to 9.3 months) in the PEGPH20 combination arm. CONCLUSION Addition of PEGPH20 to mFOLFIRINOX seems to be detrimental in patients unselected for tumor HA status. This combination caused increased toxicity (mostly GI and TE events) and resulted in decreased treatment duration compared with mFOLFIRINOX alone. The median OS in the mFOLFIRINOX control arm (14.4 months) is, to our knowledge, the longest yet reported and can be considered for patients with good PS.

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A phase IB/II randomized study of mFOLFIRINOX (mFFOX) + pegylated recombinant human hyaluronidase (PEGPH20) versus mFFOX alone in patients with good performance status metastatic pancreatic adenocarcinoma (mPC): SWOG S1313 (NCT #01959139).

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.208 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 208-208 ◽

Cited By ~ 16

Author(s):

Ramesh K. Ramanathan ◽

Shannon McDonough ◽

Philip Agop Philip ◽

Sunil R. Hingorani ◽

Jill Lacy ◽

...

Keyword(s):

Phase Ii ◽

Phase Ii Study ◽

Performance Status ◽

Randomized Study ◽

Dose Finding ◽

Type 1 Error ◽

Randomized Phase Ii ◽

Metastatic Pancreatic Adenocarcinoma ◽

Adequate Organ Function ◽

The Impact

208 Background: PEGPH20 degrades hyaluronan (HA), a major component of the stroma, increases delivery of gemcitabine and prolongs survival in preclinical models. We evaluated the activity of PEGPH20 in combination with mFFOX in mPC , unselected for tumor HA. Methods: Pertinent eligibility: untreated mPC, PS of 0-1 and adequate organ function. Standard FFOX was modified to add prophylactic growth factor support and omit bolus 5FU. Due to increased thromboembolic (TE) events with PEGPH20, an amendment instituted LMWH prophylaxis in the PEGPH20 arm only. Following a dose finding cohort of mFFOX + PEGPH20, the Phase II study randomized patients (1:1) to the combination arm or mFFOX alone (n = 138). The primary endpoint was overall survival (OS), with a null median OS of 10 mo and an alternative of 15 mo (1-sided type 1 error 0.1, 80% power). Results: PEGPH20 at 3 mcg/kg, q2 weeks was more tolerable than twice weekly dosing. The randomized phase II study began May 2015. The planned interim futility analysis when 35 deaths occurred gave a HR of 0.44 favoring the standard arm, thus the study was closed to accrual (March 2017). As of August 22, 2017 (n = 111), the estimated median OS in the mFFOX arm was 15.1 mo (95% CI 10.1-15.7) vs 7.6 mo (95% CI 4.6-9.2) in the PEGPH20 arm. Conclusions: OS in the mFFOX control arm (15.1 mo) is longest yet reported. Addition of PEGPH20 to mFFOX is not recommended for further study and appears to be detrimental (HR = 0.48). The impact of PEGPH20 on OS was unexpected and in contrast to favorable results reported for the combination of gemcitabine/nab-paclitaxel + PEGPH20 especially in the HA high cohort (Hingorani S et al. A 4008, ASCO 2017). PEGPH20 with mFFOX caused increased toxicity (mostly GI and TE events) and decreased treatment duration compared to mFFOX alone. Tumor HA content will be analyzed. Funding: NIH/NCI grants CA180888, CA180819; and in part by Halozyme Inc. Clinical trial information: 01959139. [Table: see text]

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First-MIND: A phase Ib, open-label, randomized study to assess safety of tafasitamab (tafa) or tafa + lenalidomide (LEN) in addition to R-CHOP in patients with newly diagnosed DLBCL.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.7540 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 7540-7540

Author(s):

David Belada ◽

Katerina Kopeckova ◽

Juan Miguel Bergua ◽

Marc André ◽

Ernesto Perez Persona ◽

...

Keyword(s):

Performance Status ◽

Randomized Study ◽

International Prognostic Index ◽

Prognostic Index ◽

Dose Intensity ◽

Newly Diagnosed ◽

Open Label ◽

Bulky Disease ◽

Phase Ib ◽

Ecog Ps

7540 Background: Tafasitamab is a humanized, Fc-modified anti-CD19 monoclonal antibody that enhances antibody-dependent cellular cytotoxicity and phagocytosis. It is FDA-approved with LEN for adult patients (pts) with relapsed/refractory (R/R) DLBCL ineligible for autologous stem cell transplantation. First-MIND (NCT04134936) is a Phase Ib, open-label, randomized study of tafa + R-CHOP or tafa + LEN + R-CHOP in newly diagnosed DLBCL. Methods: Eligible pts were ≥18 years, treatment-naïve, with histologically confirmed DLBCL not otherwise specified, international prognostic index (IPI) 2–5 and ECOG performance status (PS) 0–2. Pts with known double- or triple-hit and transformed lymphoma were excluded. Treatment (Tx) comprised six 21-day cycles of tafa (12 mg/kg IV, Day [D] 1, 8, 15) + R-CHOP (arm A) or tafa (12 mg/kg IV, D1, 8, 15) + LEN (25 mg orally, D1–10) + R-CHOP (arm B). G-CSF and VTE prophylaxis was mandatory. Primary objective is safety; secondary objectives are ORR, PET-CR rate at end of Tx, PFS, long-term safety, pharmacokinetics, immunogenicity. Results: From Dec 2019 to Aug 2020, 83 pts were screened in Europe and the US; 66 were randomized (33 per arm). Data cut-off for this analysis: 9 Dec 2020; study is ongoing. Median age was 64.5 years (range 20–86). Overall, 30% (20/66) of pts were ≥70 years and many had high-risk disease: IPI 2 29%, IPI 3 46%, IPI 4 26%. ECOG PS: 47% of pts were ECOG PS 0, 44% PS 1, 9% PS 2. Most pts had stage III/IV disease (92%); 46% had bulky disease. All pts experienced a treatment-emergent adverse event (TEAE). Grade ≥3 neutropenia and thrombocytopenia occurred in 54.5% and 12.1% (arm A) and 66.7% and 30.3% (arm B) of pts, respectively (Table). Serious TEAEs occurred in 42.4% (arm A) and 51.5% (arm B) of pts. There were three deaths, unrelated to tafa and/or LEN (sepsis, urosepsis, and COVID-19 pneumonia). R-CHOP dose intensity was maintained in both arms. Among 60 pts who completed tumor assessments after cycle 3, ORR was 89.7% (arm A) and 93.5% (arm B). Conclusions: These data suggest R-CHOP + tafa or tafa + LEN is tolerable in pts with Tx-naïve DLBCL and that R-CHOP dosing is not affected. Toxicities are similar to those expected with R-CHOP or R-CHOP + LEN. Updated safety and early efficacy data will be presented at the conference. Clinical trial information: NCT04134936. [Table: see text]

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Phase II Study of Uracil-Tegafur With Leucovorin in Elderly (≥ 75 years old) Patients With Colorectal Cancer: ECOG 1299

Journal of Clinical Oncology ◽

10.1200/jco.2006.10.4521 ◽

2007 ◽

Vol 25 (34) ◽

pp. 5397-5402 ◽

Cited By ~ 20

Author(s):

Howard S. Hochster ◽

Weixiu Luo ◽

Elizabeta C. Popa ◽

Bruce T. Lyman ◽

Mary Mulcahy ◽

...

Keyword(s):

Colorectal Cancer ◽

Elderly Patients ◽

Survival Time ◽

Phase Ii ◽

Performance Status ◽

Progression Free Survival ◽

Open Label ◽

Old Patients ◽

Gi Toxicity ◽

Grade 3

Purpose To evaluate the tolerability and effectiveness of uracil-tegafur (UFT) with leucovorin (LV) in the treatment of elderly patients with advanced colorectal cancer. Patients and Methods Patients ≥ 75 years of age with previously untreated colorectal cancer were eligible for this phase II, single-arm, open-label, multicenter cooperative group clinical trial. UFT 100 mg/m2 plus LV 30 mg orally every 8 hours for 28 days every 35 days was administered until progression. Results Fifty-eight patients were enrolled between June 2000 and July 2001, and 55 were treated. The median age of treated patients was 81 years (range, 75 to 90 years), 26 patients were (47%) women, and 80% had good performance status (0 to 1). The observed overall response rate was 22% (95% CI, 11.8% to 35.0%). The estimated median overall survival time was 13.0 months (95% CI, 9.6 to 17.4 months), and median progression-free survival time was 4.6 months (95% CI, 2.6 to 6.7 months). Among the 56 treated patients (including one ineligible patient), 31 (55%) experienced grade 3 to 4 toxicities, most commonly diarrhea (25%) and GI toxicity (36%), with patients older than 85 years of age at highest risk. Conclusion The results of this trial support the efficacy of oral UFT/LV in elderly patients with colorectal cancer. The regimen is tolerated moderately well overall, particularly as compared with other fluoropyrimidine regimens, although there is increased GI toxicity in the most elderly. These results suggest that studies using newer oral fluoropyrimidine analogs should be investigated in this patient population.

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A 1-Year, Open Label, Randomized Phase II Dose Finding Study of Degarelix for the Treatment of Prostate Cancer in North America

The Journal of Urology ◽

10.1016/j.juro.2008.07.033 ◽

2008 ◽

Vol 180 (5) ◽

pp. 1986-1992 ◽

Cited By ~ 67

Author(s):

Marc Gittelman ◽

Peter J. Pommerville ◽

Bo-Eric Persson ◽

Jens-Kristian Jensen ◽

Tine Kold Olesen ◽

...

Keyword(s):

Prostate Cancer ◽

North America ◽

Phase Ii ◽

Dose Finding ◽

Open Label ◽

Randomized Phase Ii ◽

Finding Study ◽

Dose Finding Study

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Safety and pharmacokinetics (PK) of AMG 706 in combination with gemcitabine for the treatment of patients (pts) with solid tumors

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.14005 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 14005-14005 ◽

Cited By ~ 2

Author(s):

T. J. Price ◽

L. Lipton ◽

J. Williams ◽

J. McGreivy ◽

S. McCoy ◽

...

Keyword(s):

Solid Tumors ◽

Maximum Tolerated Dose ◽

Dose Finding ◽

Open Label ◽

Multikinase Inhibitor ◽

Vein Thrombosis ◽

Finding Study ◽

Label Dose ◽

Grade 3 ◽

Deep Vein

14005 Background: AMG 706 is an oral, investigational multikinase inhibitor (MKI) with antiangiogenic and direct antitumor activity achieved by selectively targeting VEGF, PDGF and Kit receptors. Methods: This is a fully enrolled, phase 1b, open-label, dose- finding study. The objectives are to determine the maximum tolerated dose and to assess safety and PK of AMG 706 in pts with solid tumors receiving AMG 706 plus gemcitabine. Pts =18 years with ECOG 0–2 and no prior treatment with bevacizumab or VEGFr MKIs were assigned to cohorts receiving escalating doses of AMG 706 (50mg QD, 125mg QD or 75mg BID continuously from day 2 of cycle 1) plus gemcitabine (1000mg/m2 weekly for 7/8 wks, then 3/4 wks per cycle) for up to 11 cycles. Assessments include dose-limiting toxicities (DLT) (weeks 1–4) and tumor response (every 3 months). Results: 26 pts were enrolled and received at least 1 dose of AMG 706 (50mg QD n=11; 125mg QD n=6; 75mg BID n=9). All but 2 pts have completed the study. Median (range) age was 57 (25–77) yrs. 65% of pts received prior chemotherapy; 4 pts received prior gemcitabine (50mg QD n=2; 125mg QD n=1; 75mg BID n=1). There were 2 DLTs: grade 4 neutropenia (125mg QD), grade 3 deep vein thrombosis (75mg BID). Treatment-related adverse events (AE) occurring in = 10% of pts are shown in the table . The mean AMG 706 PK profiles were not markedly different when AMG 706 was dosed on the same day or 24 hours after gemcitabine administration. Objective tumor responses per RECIST for 26 evaluable pts were: 2 unconfirmed PR (50mg QD n=1; 125mg QD n=1), 7 SD (50mg QD n=3; 125mg QD n=1; 75mg BID n=3), 11 PD (50mg QD n=7; 125mg QD n=3; 75mg BID n=1), and 6 not available (125mg QD n=1; 75mg BID n=5). Conclusions: These preliminary data suggest that, in pts with solid tumors, AMG 706 combined with gemcitabine had an expected AE profile at the target once-daily dose of 125mg QD, with little effect on AMG 706 PK. The data provide a foundation for conducting further trials, potentially including biliary tumors. Final data will be presented. [Table: see text] No significant financial relationships to disclose.

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Activity and safety of Nab-FOLFIRI and Nab-FOLFOX as first-line treatment for metastatic pancreatic cancer (phase II NabucCO study).

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.351 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 351-351 ◽

Cited By ~ 1

Author(s):

Elisa Giommoni ◽

Evaristo Maiello ◽

Vanja Vaccaro ◽

Ermanno Rondini ◽

Caterina Vivaldi ◽

...

Keyword(s):

Pancreatic Cancer ◽

Phase Ii ◽

Progression Free Survival ◽

Maximum Tolerated Dose ◽

Dose Finding ◽

Phase Iii ◽

Metastatic Pancreatic Cancer ◽

First Line ◽

Open Label ◽

Grade 3

351 Background: FOLFIRINOX is an approved regimen for metastatic pancreatic cancer (mPC). We performed a modification in FOLFIRINOX schedule, using nab-paclitaxel (nab-p) to obtain two regimens that could be as effective and less toxic than the original triplet. NabucCO study was a randomized phase II trial to assess activity and toxicity of nab-p instead of either oxaliplatin (Nab-FOLFIRI) or irinotecan (Nab-FOLFOX) in first line setting. Previous dose–finding NabucCO study defined that maximum tolerated dose of nab-p with FOLFIRI is 120 mg/m2, and with FOLFOX is 160 mg/m2. Methods: The study was a 1:1 parallel arm, open label, not comparative one to assess overall response rate (ORR) of Nab-FOLFIRI and Nab-FOLFOX as primary end-point. Patients (pts) with PS 0-1, untreated for mPC were randomized to receive leucovorin 400 mg/m2, 5FU bolus 400 mg/m2, 5FU 48h ci 2400 mg/m2, irinotecan 180 mg/m2 plus nab-p 120 mg/m2 (arm A) or leucovorin 400 mg/m2, 5FU bolus 400 mg/m2, 5FU 48h ci 2400 mg/m2 and oxaliplatin 85 mg/m2 iv plus nab-p 160 mg/m2 (arm B) every 2 weeks for up to 12 cycles. Secondary end points were clinical benefit rate (CBR), progression free survival (PFS), overall survival (OS), and safety. Results: From November 2015 to January 2017, 84 pts were treated (42 for each arm). Median age was 60 years (29-65) in arm A and 64 years (47-64) in arm B. The ORR was 31 % for both schedules, with a CBR of 69% and 71%, respectively. At a median follow-up of 11.4 months for arm A and 14.5 months for arm B (censored on august, 31th 2017), 1-year survival is 41% and 50%, respectively. For Nab-FOLFIRI PFS and mOS were 6 months (90% CI: 4.9-8.0) and 13.2 months (90% CI: 8.3-14.8), while in Nab-FOLFOX were 5.6 months (90% CI:4.9-7.2) and 10.8 months (90% CI: 8.4-12.8). Grade ≥3 toxicities in arm A were neutropenia (19%) and febrile neutropenia (12%). In arm B, main grade ≥3 toxicities were neutropenia (29%), fatigue (14%), peripheral neuropathy (7%). No toxic death were registered. Conclusions: Nab-FOLFIRI and Nab–FOLFOX demonstrated a similar activity to FOLFIRINOX, with better safety profile in terms of neutropenia, fatigue and neuropathy. These results could justify a future phase III evaluation. Clinical trial information: NCT02109341.

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XELOX with bevacizumab in elderly patients age 75 or older with metastatic colorectal cancer: Results of a planned interim analysis for multicenter phase II ASCA study.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.4_suppl.502 ◽

2013 ◽

Vol 31 (4_suppl) ◽

pp. 502-502 ◽

Cited By ~ 2

Author(s):

Keiichiro Ishibashi ◽

Yoshinori Munemoto ◽

Masaki Matsuoka ◽

Taishi Hata ◽

Michiya Kobayashi ◽

...

Keyword(s):

Colorectal Cancer ◽

Renal Function ◽

Elderly Patients ◽

Metastatic Colorectal Cancer ◽

Phase Ii ◽

Performance Status ◽

Primary Objective ◽

Open Label ◽

Ecog Performance Status ◽

Grade 3

502 Background: Combination chemotherapy of capecitabine plus oxaliplatin (XELOX) with bevacizumab is commonly used as standard chemotherapy for metastatic colorectal cancer (mCRC). A previous meta-analysis showed that there was no difference between two age groups of <65 years and ≥65 years on overall survival (OS) after treatment with chemotherapy with bevacizumab. However, the safety and efficacy of XELOX with bevacizumab in elderly patients (pts) ≥75 years with mCRC remain unclear. Methods: This study was an open-label multicentre phase II study to evaluate the efficacy and safety of XELOX with bevacizumab in pts ≥75 years with metastatic CRC. The primary objective was to assess progression-free survival (PFS). The secondary endpoints were the safety, response rate (RR), time to treatment-failure (TTF) and OS. Results: 36 pts were enrolled. Pts characteristics were; median age 78 (range 75-86); male/female, 21/15; ECOG performance status 0/1, 30/6; colon/rectum 24/12, creatinine clearance (CCr) 60.2 ml/min (range 32.6-84.6). Median follow-up period was 220 days. RR was 55.6% and median TTF was 209 days. The median PFS and median OS are not reached. Grade 3 or 4 adverse events (AEs) were reported in 22 pts (62.8%). Common grade 3 or 4 AEs were hypertension (11.4%), leukopenia (20.0%), peripheral sensory neuropathy (14.3%), hand foot syndrome (8.6%), and fatigue (8.6%). Examining the relationship between renal function (CCr) and AEs, the incidence of Grade 3 or 4 AEs in the lower CCr group was significantly higher than that in the higher CCr group (61.6% vs. 47.8%; p=0.013); hematological toxicities (87.5% vs. 14.8%; p=0.0003) and non-hematological toxicities (61.5% vs. 11.1%; p=0.018). Conclusions: XELOX with bevacizumab is safely administered in elderly patients ≥75 years. Renal function (CCr) could be a good predictive marker for grade 3 or 4 AEs. Clinical trial information: UMIN000003500.

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Anlotinib and irinotecan for advanced Ewing sarcoma after failure of standard therapy: A multicenter, two-cohort, single-arm, open label, phase Ib/II trial (NCT03416517).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.11012 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 11012-11012

Author(s):

Jie Xu ◽

Lu Xie ◽

Wei Guo ◽

Xiaodong Tang ◽

Rongli Yang ◽

...

Keyword(s):

Phase Ii ◽

Ewing Sarcoma ◽

Initial Level ◽

Objective Response ◽

Complete Response ◽

Fixed Dose ◽

Open Label ◽

Phase Ib ◽

Open Label Phase ◽

Grade 3

11012 Background: Both protracted irinotecan and anti-angiogenesis therapy have shown promising results in Ewing sarcoma. We did this phase Ib/II trial to first define the proper dose of irinotecan in combination with anlotinib in Ewing sarcoma and then evaluate efficacy. Methods: Patients diagnosed with recurrent or refractory Ewing sarcoma were enrolled and sub-classified into cohort A (≥16y) or cohort B ( < 16y). In the dose-defining phase Ib portion, anlotinib was given at a fixed dose of 12mg D1-14every 21 days, while the de-escalated 3+3 design was used to detect the recommended dose of irinotecan in each cohort from an initial level of 20mg/m2/d dx5x2. Recommended phase 2 dose (RP2D) was defined as the highest dose at which no more than 30% patients experience a DLT in the first two courses. In the next dose-expanding phase II portion, the primary endpoint was objective response rate at 12 weeks (ORR12w). A conventional two-stage study design model was used. Results: 41 patients were enrolled with 29 in cohort A and 12 in cohort B. For cohort A, first 5 patients were treated at initial level in phase Ib portion, two of whom subsequently experienced delayed diarrhea as dose-limiting toxicity (DLT). Additional six patients were then treated at a lower dose of 15mg/m2. Since no more DLT was recorded, it was used as RP2D. 23/24 patients in cohort A phase II were available for response evaluation at 12 weeks, with one complete response (CR), 14 partial response (PR) (including one CMR who has a negative PET/CT scan but still abnormal lesions in MR scan), 2 stable disease (SD) and 6 progressive disease (PD). ORR12wwas 62.5%. For cohort B, no DLT was noticed in the first six patients treated at the initial level which was used as RP2D later. Finally, 12 patients were included in cohort B. ORR12wwas 83.3% with two CR, 8 PR (including one CMR) and two PD. Although effective, cohort B were closed because of slow enrollment. Most common grade 3/4 adverse events were diarrhea, abdominal pain and neutropenia. The genotype of UGT1A1*1 and UGT1A1*28 were not associated with the risk of diarrhea. Conclusions: The combination of irinotecan and anlotinib demonstrated an acceptable toxicity profile with promising evidence of clinical efficacy in advanced Ewing sarcoma. Clinical trial information: NCT03416517.

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