Phase 3, open-label, randomized study of first-line pembrolizumab (pembro) vs investigator-choice chemotherapy for mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) metastatic colorectal carcinoma (mCRC): KEYNOTE-177.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS3618-TPS3618 ◽  
Author(s):  
Luis A. Diaz ◽  
Dung T. Le ◽  
Takayuki Yoshino ◽  
Thierry Andre ◽  
Johanna C. Bendell ◽  
...  
Keyword(s):  
Disease Progression ◽  
Performance Status ◽  
Randomized Study ◽  
Immune Checkpoints ◽  
First Line ◽  
Open Label ◽  
Phase 3 ◽  
Ecog Performance Status ◽  
End Points ◽  
To Receive

TPS3618 Background: About 5% of mCRCs are dMMR, leading to high levels of MSI. CRCs with MSI-H have abundant lymphocyte infiltrates and strong expression of immune checkpoints. In the phase 2 KEYNOTE-016 study, the anti-programmed death 1 (PD-1) antibody pembro provided an ORR of 40% in patients (pts) with progressive dMMR mCRC vs 0% in pts with MMR-proficient mCRC. KEYNOTE-177 (ClinicalTrials.gov, NCT02563002) is an international, randomized, open-label, phase 3 study designed to evaluate the efficacy and safety of pembro vs standard-of-care (SOC) chemotherapy in the first-line setting for dMMR or MSI-H mCRC. Methods: Key eligibility criteria include age ≥ 18 years, locally confirmed dMMR or MSI-H stage IV CRC, measurable disease per RECIST v1.1 by local site assessment, ECOG performance status 0-1, no active autoimmune disease or brain metastases, and no prior therapy for mCRC. Pts are to be randomized 1:1 to receive either pembro 200 mg Q3W or investigator’s choice of SOC chemotherapy, which must be chosen prior to randomization; options include mFOLFOX6 or FOLFIRI alone or in combination with bevacizumab or cetuximab. Treatment is to continue until disease progression, unacceptable toxicity, pt/investigator decision, or completion of 35 cycles (pembro only). Response is to be evaluated Q9W per RECIST v1.1 by central imaging vendor review and per RECIST adapted for immunotherapy response patterns. Pts in the SOC arm who have disease progression and meet crossover criteria may be eligible to receive pembro for up to 17 treatment cycles. Eligible pts may continue pembro beyond initial RECIST-defined progression. AEs are to be assessed throughout treatment and for 30 days thereafter (90 days for serious AEs) and graded per NCI CTCAE v4.0. Pts are to be followed for survival Q9W. Primary end point is PFS per RECIST v1.1 by central imaging vendor review. Secondary end points include ORR per RECIST v1.1 by central imaging vendor review, OS, and safety and tolerability. Other end points include DOR and HRQoL. Planned enrollment in KEYNOTE-177 is 270 pts across 21 countries. Clinical trial information: NCT02563002.

KEYNOTE-177: Phase 3, open-label, randomized study of first-line pembrolizumab (Pembro) versus investigator-choice chemotherapy for mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) metastatic colorectal carcinoma (mCRC).

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. TPS877-TPS877 ◽  
Author(s):  
Luis A. Diaz ◽  
Dung T. Le ◽  
Takayuki Yoshino ◽  
Thierry André ◽  
Johanna C. Bendell ◽  
...  
Keyword(s):  
Disease Progression ◽  
Performance Status ◽  
Randomized Study ◽  
Immune Checkpoints ◽  
First Line ◽  
Open Label ◽  
Phase 3 ◽  
Ecog Performance Status ◽  
End Points ◽  
To Receive

TPS877 Background: Approximately 5% of mCRCs are dMMR, leading to high levels of MSI. CRCs with MSI-H have abundant lymphocyte infiltrates and strong expression of immune checkpoints. In the phase 2 KEYNOTE-016 study, the anti–programmed death 1 (PD-1) antibody pembro provided an ORR of 40% in patients (pts) with progressive dMMR mCRC vs 0% in pts with MMR-proficient mCRC. KEYNOTE-177 (ClinicalTrials.gov, NCT02563002) is an international, randomized, open-label, phase 3 study to evaluate the efficacy and safety of pembro vs standard-of-care (SOC) chemotherapy as first-line therapy for dMMR or MSI-H mCRC. Methods: Pts aged ≥18 years with locally confirmed dMMR or MSI-H stage IV CRC, measurable disease per RECIST v1.1 by local site assessment, ECOG performance status 0-1, adequate organ function, no active autoimmune disease or brain metastases, and no prior systemic therapy for mCRC are eligible. Pts will be randomized 1:1 to receive pembro 200 mg every 3 weeks (Q3W) or investigator’s choice of SOC chemotherapy (options include mFOLFOX6 or FOLFIRI alone or in combination with bevacizumab or cetuximab; must be chosen prior to randomization). Treatment will continue until disease progression, unacceptable toxicity, pt/investigator decision to withdrawal, or completion of 35 cycles (pembro only). Response will be evaluated Q9W per RECIST v1.1 by central imaging vendor review and per immune-related RECIST. Pts in the SOC arm who have disease progression and meet crossover criteria may be eligible to receive pembro for up to 17 treatment cycles. Eligible pts may continue pembro after initial RECIST-defined progression. AEs will be assessed throughout treatment and for 30 days thereafter (90 days for serious AEs) and graded per NCI CTCAE v4.0. Pts are to be followed up for survival Q9W. Primary end point is PFS per RECIST v1.1 by central imaging vendor review. Secondary end points include ORR per RECIST v1.1 by central imaging vendor review, OS, and safety and tolerability. Other end points include DOR and HRQoL. Planned enrollment in KEYNOTE-177 is 270 pts across 23 countries. Clinical trial information: NCT02563002.

Phase III LEAP-010 study: first-line pembrolizumab with or without lenvatinib in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS6589-TPS6589 ◽  
Author(s):  
Lillian L. Siu ◽  
Barbara Burtness ◽  
Ezra E.W. Cohen ◽  
Kevin Joseph Harrington ◽  
Lisa F. Licitra ◽  
...  
Keyword(s):  
Disease Progression ◽  
Tumor Imaging ◽  
Performance Status ◽  
Objective Response ◽  
Phase Iii ◽  
First Line ◽  
Ecog Performance Status ◽  
Double Blind ◽  
Multikinase Inhibitor ◽  
End Points

TPS6589 Background: The PD-1 inhibitor pembrolizumab is currently approved as first-line monotherapy for patients with R/M HNSCC whose tumors express PD-L1 combined positive score (CPS) ≥1. In a phase 1b/2 trial (NCT02501096) of pembrolizumab plus lenvatinib (multikinase inhibitor of VEGFR 1-3, FGFR 1-4, PDGFRa, RET, and KIT) in solid tumors, the combination demonstrated promising antitumor activity and a manageable safety profile in patients with HNSCC. LEAP-010 (NCT04199104) is a randomized, double-blind, placebo-controlled, phase 3 study that will evaluate the efficacy and safety of first-line pembrolizumab with or without lenvatinib in patients with PD-L1–positive R/M HNSCC. Methods: Key eligibility criteria include histologically confirmed R/M HNSCC incurable by local therapies, PD-L1–positive tumor (CPS ≥1) as determined by central laboratory, measurable disease as assessed by blinded independent central review (BICR) per RECIST v1.1, and ECOG performance status (PS) 0 or 1. Patients will be randomly assigned 1:1 to pembrolizumab plus lenvatinib or pembrolizumab plus placebo. Randomization will be stratified by PD-L1 status defined by tumor proportion score ( < 50% vs ≥50%), human papillomavirus status for oropharynx cancer (positive vs negative), and ECOG PS (0 or 1). Patients will receive intravenous pembrolizumab 200 mg every 3 weeks for 35 cycles (~2 years) and oral lenvatinib 20 mg or placebo once daily; patients may continue to receive lenvatinib or placebo after pembrolizumab treatment is complete. Treatment will continue until BICR-verified disease progression or unacceptable toxicity. Pembrolizumab retreatment (second course) for 17 additional cycles will be allowed for eligible patients who stop pembrolizumab and subsequently experience BICR-verified disease progression. These patients could have stopped treatment with stable disease, partial response, or complete response or after 35 cycles of pembrolizumab for reasons other than disease progression or toxicity. Tumor imaging assessment will be performed at week 6, then every 6 weeks until 1 year, and thereafter every 9 weeks. Primary end points are objective response rate and progression-free survival, assessed by BICR per RECIST v1.1, and overall survival. Secondary end points are duration of response and safety and tolerability. Recruitment is ongoing; planned enrollment is ~500 patients. Clinical trial information: NCT04199104 .

Phase II, open-label, randomized study of first-line zolbetuximab plus gemcitabine and nab-paclitaxel (GN) in Claudin 18.2–positive metastatic pancreatic cancer (mPC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS4667-TPS4667
Author(s):  
Wungki Park ◽  
Eileen Mary O'Reilly ◽  
Junji Furuse ◽  
Futoshi Kunieda ◽  
Fei Jie ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Performance Status ◽  
Randomized Study ◽  
Objective Response ◽  
Tolerability Profile ◽  
Phase 2 ◽  
First Line ◽  
Open Label ◽  
Ecog Performance Status ◽  
Junction Protein

TPS4667 Background: Combinations of folinic acid, fluorouracil (5-FU), irinotecan, and oxaliplatin (FOLFIRINOX) along with GN are standard first-line treatment options for mPC. Despite treatment advances, mPC has a poor prognosis with a 5-year survival rate of < 5%, emphasizing an urgent need for new targeted therapeutics. Claudin 18.2 (CLDN18.2) is a tight junction protein restricted to normal gastric mucosa cells; however, in the context of malignant transformation, CLDN18.2 is frequently expressed in carcinomas derived from organs that do not normally express it, such as pancreatic adenocarcinoma (50-70% express CLDN18.2). Zolbetuximab is a chimeric IgG1 monoclonal antibody that specifically binds to CLDN18.2, designed to mediate cancer cell death through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Methods: This phase 2 study (NCT03816163) with a safety lead-in phase will assess safety and antitumor activity of zolbetuximab plus GN in patients (pts) with histologically confirmed mPC with high CLDN18.2 expression (≥75% of tumor cells demonstrate moderate-to-strong IHC staining). The safety lead-in will assess safety/tolerability of zolbetuximab (n = 3 at 1,000 mg/m2 on Cycle 1 Day 1 then 600 mg/m2 Q2W then expand/de-escalate using a 3+3 design) plus GN and confirm the recommended phase 2 dose (RP2D). Dose-limiting toxicities (DLTs), defined as a specified toxicity that occurs during the DLT assessment period and is related to zolbetuximab, will be assessed after Cycle 1 (28 days). After determining the RP2D, approximately 129 pts will be randomly assigned 2:1 to receive either zolbetuximab RP2D Q2W on Days 1 and 15 plus GN on Days 1, 8, and 15 of each cycle ( Arm 1), or GN alone on Days 1, 8, and 15 of each cycle ( Arm 2). Randomization will be stratified by ECOG performance status (0 or 1) and liver metastasis (yes or no). Imaging (CT/MRI) will be performed at baseline and every 8 weeks until investigator-assessed disease progression (per RECIST v1.1 criteria) or the start of other systemic anticancer treatment, whichever comes earlier. Primary objectives are to confirm RP2D (safety lead-in), to assess antitumor activity measured by overall survival (randomization phase), and to establish the safety/tolerability profile of zolbetuximab plus GN across the study. Key secondary endpoints in the randomization phase are progression-free survival and objective response rate. As of January 2020, this study is recruiting pts at 74 centers. Clinical trial information: NCT03816163 .

Update results from ALTER-C-001: Efficacy and safety of anlotinib plus XELOX regimen as first-line treatment followed by maintenance monotherapy of anlotinib for patients with mCRC-A single-arm, multicenter, phase Ⅱ clinical trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15550-e15550
Author(s):  
Jin Yan ◽  
Yunwei Han ◽  
Li Zhang ◽  
Yongdong Jin ◽  
Hao Sun
Keyword(s):  
Clinical Trial ◽  
Adverse Events ◽  
Performance Status ◽  
Phase Iii ◽  
Line Treatment ◽  
First Line ◽  
Open Label ◽  
Ecog Performance Status ◽  
Multicenter Phase ◽  
First Line Treatment

e15550 Background: The combination of anti-VEGF or anti-EGFR targeted drugs with chemotherapy is the standard first-line therapy for metastatic colorectal cancer (mCRC), and the followed maintenance treatment is an optional approach to balance the efficacy and toxicity. However, studies regarding the maintenance strategies based on antiangiogenic TKIs are limited currently. Anlotinib, a novel oral multi-target TKI which can inhibit both tumor angiogenesis and tumor cell proliferation simultaneously, substantially prolonged the PFS with manageable toxicity for refractory mCRC in the phase III ALTER0703 clinical trial. Here we report an update on the effectiveness and safety of anlotinib plus XELOX as first-line treatment followed by anlotinib monotherapy for mCRC. Methods: In this open label, single-arm, multicenter phase II clinical trial, 53 mCRC patients without prior systemic treated, aged 18-75 and an ECOG performance status of 0 or 1 were planned to recruit. Eligible patients received capecitabine (1000 mg/m2, po, d1-14, q3w) and oxaliplatin (130 mg/m2, iv, d1, q3w) plus anlotinib (10mg, po, d1̃14, q3w) treatment for 6 cycles. After 6 cycles of inducing therapy, patients would receive anlotinib (12mg, po, d1̃14, q3w) as maintenance therapy until disease progression or intolerable adverse events (AEs). The primary endpoint was PFS; Secondary endpoints included ORR, DCR, DOR and safety. Results: By the data analysis cutoff date of January 22, 2021, a total of 18 patients were enrolled, of which 12 patients were available for efficacy assessment. In best overall response assessment, there were 50.0% PR (6/12), 33.3% SD (4/12) and 16.7% PD (2/12). The ORR was 50.0% (95% CI, 21.1-78.9%) and DCR was 83.3% (95% CI, 51.5-97.9%). The longest duration of treatment was 8.8 months and the response was still ongoing. The median PFS was not reached. The most common treatment related adverse events (TRAEs) of any grade (≥20%) were leukopenia, hypertension, neutropenia, diarrhea, fatigue, hypertriglyceridemia. Grade 3/4 TRAEs included hypertension (22.2%), hypertriglyceridemia (11.1%), lipase elevated (11.1%) and neutropenia (5.6%). No grade 5 AEs occurred. Conclusions: The update results suggested that anlotinib combined with XELOX as first line regimen followed by anlotinib monotherapy showed promising anti-tumor activity and manageable safety for patients with mCRC. And the conclusions needed to be confirmed in trials continued subsequently. Clinical trial information: ChiCTR1900028417.

Phase 3 clinical Trial Evaluating 90y glass microspheres in patients with metastatic colorectal carcinoma of the liver who have failed first-line chemotherapy.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 474-474
Author(s):  
Maria Angela Karpf
Keyword(s):  
Clinical Trial ◽  
Performance Status ◽  
Randomized Study ◽  
Progression Free Survival ◽  
Second Line ◽  
Glass Microspheres ◽  
First Line ◽  
Phase 3 ◽  
Free Survival ◽  
Line Chemotherapy

474 Background: Colorectal cancer (CRC) is the third most common cancer in the US. Half of pts diagnosed with CRC develop liver disease. Unresectable liver metastases are responsible for morbidity/mortality. Typically, pts with metastatic CRC receive an oxaliplatin- or irinotecan-based regimen as first-line chemotherapy, +/- bevacizumab. On progression, pts are treated with the regimen they did not receive during first-line chemo. A study to evaluate yttrium 90 glass microspheres (TheraSphere; 90Y) in pts with unresectable mCRC of the liver showed that pts with good performance status, no extrahepatic metastases, and ≤ 25% tumor may benefit most from 90Y. 90Y glass microspheres are approved by FDA under a Humanitarian Device Exemption (HDE). This study will evaluate outcomes in this patient subset when 90Y is added to second-line SOC chemo. The objective is to evaluate efficacy/safety of 90Y in patients with liver mCRC that has progressed after first-line chemo. Methods: Open-label, multi-center, randomized study to evaluate 90Y treatment in ~340 eligible pts, in whom SOC 2nd-line chemo with either an oxaliplatin or irinotecan-based regimen is planned. Eligible pts will be randomized 1:1 to control or treatment. Treatment pts will receive a first cycle of second-line chemo within 21 days of randomization and at least 14 days after the last dose of first-line agents including VEGF inhibitors. 90Y will be administered in place of the second chemotherapy cycle. Control pts will receive planned SOC second-line chemo. Primary endpoint is progression-free survival. Secondary: overall survival, hepatic progression-free survival, time to symptomatic progression, tumor response rate, and adverse events. Pts will have regular study visits as long as they participate, at which time safety/efficacy data will be collected and recorded. Results: NA Conclusions: Given the potential benefit to mCRC pts, this Phase 3 study will evaluate 90Y in the second-line setting in patients who have progressed following SOC first-line chemotherapy. Clinical trial information: NCT01483027.

PACIFIC-2: Phase 3 study of concurrent durvalumab and platinum-based chemoradiotherapy in patients with unresectable, stage III NSCLC.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS8573-TPS8573 ◽  
Author(s):  
Jeffrey D. Bradley ◽  
Makoto Nishio ◽  
Isamu Okamoto ◽  
Michael David Newton ◽  
Leonardo Trani ◽  
...  
Keyword(s):  
Performance Status ◽  
Objective Response ◽  
Additional Benefit ◽  
Stage Iii ◽  
Phase 3 ◽  
Ecog Performance Status ◽  
Double Blind ◽  
Unresectable Stage ◽  
Stage Iii Nsclc ◽  
To Receive

TPS8573 Background: Durvalumab, a selective, high-affinity, engineered human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80, is approved in the US, Japan and several other countries, for the treatment of patients (pts) with unresectable, stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent chemoradiotherapy (cCRT). These approvals were based on results from the phase 3 PACIFIC study, in which durvalumab was given 1–42 days after completion of definitive cCRT and significantly improved progression-free survival (PFS) vs placebo (median 16.8 vs 5.6 months; HR 0.52, 95% CI 0.42– 0.65; p<0.001) and overall survival (OS) vs placebo (stratified HR 0.68; 99.73% CI 0.47–0.997; p=0.0025). Increasing evidence suggests additional benefit when anti-PD-1/PD-L1 therapies are administered alongside cCRT. The PACIFIC 2 study therefore aims to assess whether durvalumab plus cCRT provides additional benefit, in terms of PFS and objective response rate (ORR), compared with cCRT alone. Methods: PACIFIC 2 is a phase 3, randomized, double-blind, placebo-controlled, multicenter, international study. Approximately 300 pts with unresectable stage III NSCLC will be randomized (2:1) to receive either durvalumab (intravenous 1500 mg) every 4 weeks (q4w) + cCRT, or placebo q4w + cCRT. Eligible pts must have histologically or cytologically confirmed stage III disease; ECOG performance status 0 or 1; and life expectancy >12 weeks at randomization. Pts who discontinue treatment will be followed for safety and OS. Primary endpoints are PFS and ORR (RECIST v1.1) assessed via blinded independent central review. Secondary endpoints include OS; OS at month 24; complete response (CR) rate; duration of response; disease control rate; time to death/distant metastases; time from randomization to second progression; safety; and symptoms, functioning and global health status. Pts with a CR, partial response or stable disease will continue to receive durvalumab or placebo until clinical or RECIST v1.1-defined disease progression, or until another discontinuation criterion is met. Study enrollment began in March 2018 and recruitment is ongoing. Clinical trial information: NCT03519971.

Phase 3, randomized study of pembrolizumab (pembro) vs best supportive care (BSC) for second-line advanced hepatocellular carcinoma (HCC): KEYNOTE-240.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS4143-TPS4143 ◽  
Author(s):  
Richard S. Finn ◽  
Stephen L. Chan ◽  
Andrew X. Zhu ◽  
Jennifer J. Knox ◽  
Ann-Lii Cheng ◽  
...  
Keyword(s):  
Disease Progression ◽  
Kinase Inhibitor ◽  
Performance Status ◽  
Randomized Study ◽  
Objective Response ◽  
Local Treatment ◽  
Standard Of Care ◽  
Advanced Hepatocellular Carcinoma ◽  
Phase 3 ◽  
Double Blind

TPS4143 Background: The tyrosine kinase inhibitor sorafenib is the standard of care for first-line HCC; currently, there is no clear standard of care after disease progression on sorafenib or for patients (pts) with intolerance to sorafenib. Because most HCC is driven by inflammation, there is a strong rationale to evaluate immunotherapy in pts with this type of cancer. The randomized, double-blind, placebo-controlled phase 3 KEYNOTE-240 study (ClinicalTrials.gov, NCT02702401) was designed to compare the efficacy and safety of the anti–PD-1 antibody pembro + BSC vs placebo + BSC in pts with previously treated advanced HCC. Methods: Eligibility criteria include age ≥ 18 years, histologically or cytologically confirmed diagnosis of HCC, documented progression after stopping treatment with sorafenib or intolerance to sorafenib, disease not amenable to a curative treatmentapproach (eg, transplantation, surgery, or ablation), measurable disease confirmed by central imaging vendor review per RECIST v1.1, Child-Pugh liver score A, ECOG performance status 0-1, and predicted life expectancy > 3 months. Pts will be randomly assigned 2:1 to receive pembro 200 mg IV Q3W + BSC or placebo Q3W + BSC for up to 35 cycles (~2 years) or until disease progression, unacceptable toxicity, or investigator decision. Randomization will be stratified by geographic region, presence of macrovascular invasion, and α-fetoprotein level. BSC will be provided by the investigator per local treatment practices. Response will be assessed every 6 weeks per RECIST v1.1 by central imaging vendor review. Adverse events (AEs) will be assessed throughout treatment and for 30 days thereafter (90 days for serious AEs) and graded per NCI CTCAE v4.0. Primary objectives are comparison of progression-free survival per RECIST v1.1 by central imaging vendor review and overall survival between treatment arms. Secondary objectives are comparison of objective response rate, duration of response, disease control rate, and time to progression per RECIST v1.1 by central imaging vendor review; and evaluation of safety and tolerability. Planned enrollment in KEYNOTE-240 is 408 pts across 26 countries. Clinical trial information: NCT02702401.

A phase III study of futibatinib (TAS-120) versus gemcitabine-cisplatin (gem-cis) chemotherapy as first-line (1L) treatment for patients (pts) with advanced (adv) cholangiocarcinoma (CCA) harboring fibroblast growth factor receptor 2 (FGFR2) gene rearrangements (FOENIX-CCA3).

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. TPS600-TPS600 ◽  
Author(s):  
Mitesh J. Borad ◽  
John A. Bridgewater ◽  
Chigusa Morizane ◽  
Rachna T. Shroff ◽  
Do-Youn Oh ◽  
...  
Keyword(s):  
Disease Progression ◽  
Performance Status ◽  
Objective Response ◽  
Phase Iii ◽  
Clinical Activity ◽  
Gene Rearrangements ◽  
Open Label ◽  
Phase 3 ◽  
Fgfr2 Gene ◽  
Ectopic Mineralization

TPS600 Background: Pts with adv CCA have poor survival outcomes, and chemotherapy offers limited survival benefit (5-year survival rates, 5–10%; median overall survival [OS], 8–12 months). FGFR2 gene rearrangements are known to be early drivers of oncogenesis in ~15% of pts with intrahepatic (i) CCA. Futibatinib, an oral, highly selective, irreversible FGFR1-4 inhibitor has shown antitumor activity against a broad spectrum of FGFR-deregulated tumors in preclinical studies. In a previous study, futibatinib demonstrated clinical activity and tolerability in heavily pretreated pts with adv CCA harboring FGFR2 gene rearrangements. This phase 3 trial (FOENIX-CCA3) is designed to evaluate futibatinib vs gem-cis as 1L therapy for pts with adv iCCA harboring FGFR2 rearrangements. Methods: FOENIX-CCA3 is a multicenter, open-label, randomized phase 3 study that will be conducted in pts with metastatic or unresectable iCCA harboring FGFR2 rearrangements (assessed at screening by a central laboratory). Pts must have an ECOG performance status of 0 or 1 and should not have received previous systemic anticancer therapy for adv disease (adjuvant/neoadjuvant therapy ≥6 mo prior to randomization is permissible). Pts with clinically-significant alterations in calcium-phosphorus homeostasis or ectopic mineralization/calcification will be excluded. Approximately 216 pts will be randomized (1:1 ratio) to receive 20 mg futibatinib once daily until disease progression or other discontinuation criteria are met or gem-cis (on days 1 and 8 of a 21-day cycle) for 8 cycles or until disease progression, whichever occurs first. Pts will be stratified by prior surgical excision (yes vs no), geographic region, and locally adv vs metastatic disease. The primary endpoint is progression-free survival (PFS) assessed by independent central review (ICR). Secondary endpoints include objective response rate and disease control rate based on ICR, OS, PFS per investigator assessment, and safety. The anticipated start date is in April, 2020.

Dasatinib in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma: Preliminary Results of a Phase I Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1876-1876 ◽  
Author(s):  
Thierry Facon ◽  
Xavier Leleu ◽  
A. Keith Stewart ◽  
Andrew Spencer ◽  
Philip Rowlings ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Board Of Directors ◽  
Performance Status ◽  
Randomized Study ◽  
Single Agent ◽  
Open Label ◽  
Ecog Performance Status ◽  
Advisory Committees ◽  
Minor Response

Abstract Abstract 1876 Poster Board I-901 Background: Multiple Myeloma (MM) remains incurable in spite of new effective agents and combination regimens. SRC family kinases (SFK) are potential targets for therapy in MM: Hck, Fyn and Lyn are implicated in IL6-induced proliferation. Dasatinib is a potent inhibitor of not only BCR-ABL, but also SFK, c-KIT, PDGFRb, and EPHA. In myeloma and endothelial cells (ECs) isolated from MM patients (pts), dasatinib blocked proliferation, survival, adhesion, migration, and angiogenic potential, through a combined targeting of PDGFRβ as well as VEGF-triggered phosphorylation of SRC. Lenalidomide has clinical efficacy in the treatment of multiple myeloma (MM) as a single agent and in combination with dexamethasone. The combination of dasatinib, lenalidomide and dexamethasone exhibits synergistic inhibition of MMIS cells. Methods: The primary objective of this Phase I, multicenter, open-label, non-randomized study was to determine the maximum tolerated dose (MTD) of the combination of dasatinib, with lenalidomide and dexamethasone in pts with relapsed or refractory (RR) MM. Secondary objectives were to assess the tolerability of the combination, to establish the dose for future clinical investigations, and to assess the efficacy by International Uniform Response and EBMT Criteria. Pts ≥18 years with confirmed RR MM, measurable disease (at least 1 g/dL for IgG or 0.5 g/dL for IgA in serum or urinary excretion of 200 mg monoclonal light chain/24 hours), and at least one prior treatment were enrolled sequentially into increasing dose cohorts (using a 3+3 design). Pts received oral dasatinib daily on a continuous schedule, oral lenalidomide daily for 21 days, and oral dexamethasone 40 mg/day (Days 1, 8, 15, and 22). Cycles were repeated every 28 days. Dose-limiting toxicities (DLTs) were assessed in the first cycle. If there was no DLT, dose escalation continued to MTD, followed by an expansion phase of the established dose. Results: Enrollment is ongoing. 16 pts (6 M, 10 F; median age 70.5 years, range 51–80) were treated in cohorts 1, 2, 3 and 4; MTD has not been established (as by July 2009). The median number of prior lines of therapy was 3 (range 1–6). Seven pts had prior autologous stem cell transplantation; 8 pts had prior thalidomide, 4 prior lenalidomide and 3 pts both. Baseline β2 microglobulin levels of >3.5mg/L were reported in 4 pts. The most common (310%) treatment related adverse events (AEs) diarrhea 6 (38%); nausea 4 (25%); constipation 2 (13%); stomatitis 2 (13%); asthenia 3 (19%); weight decrease 5 (31%); dyspnea 2 (13%); rash 2 (13%); vertigo 2 (13%); insomnia 2 (13%). The most common grade 3 / 4 hematologic AEs included neutropenia 6 (38%), anemia 4 (25%) and thrombocytopenia 3 (19%). Two DLTs were identified in cohorts 1 and 4: 1 pt had 2 point decline in ECOG Performance Status and other pt had a drug interruption > 15 days due to nausea and vomiting, respectively. Six out of 16 pts discontinued treatment: 1 due to death in first cycle (D19); 3 for AEs (2 study drug related and 1 unrelated), 1 withdrawal of consent, 1 following maximal clinical benefit (minor response) after 12+ cycles. As of July 2009, 10 pts remain on treatment, with a median duration of treatment of 4.2 months (range 0.6–12). Responses were observed in 13 pts: 8 partial responses (PR), and 5 minor responses (MR). 1 pt had stable disease (SD) and 2 pts were not evaluable (1 pts died before completion of cycle 1 and other pt was too early for assessment). Conclusion: Dasatinib in combination with lenalidomide and dexamethasone is well tolerated and preliminary activity has been observed. Disclosures: Facon: Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Stewart:Takeda-Millenium, Celgene, Novartis, Amgen: Consultancy; Takeda, Millenium: Research Funding; Genzyme, Celgene, Millenium, Proteolix: Honoraria. Garzon:BMS: Employment. Bleickardt:BMS: Employment. Gialelis:BMS: Employment. Tuozzoli:BMS: Employment. Derreumaux:BMS: Employment. Sonneveld:Janssen-Cilag: Honoraria.

Pembrolizumab plus chemotherapy for previously untreated, HER2-negative unresectable or metastatic advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: KEYNOTE-859.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. TPS263-TPS263
Author(s):  
Josep Tabernero ◽  
Yung-Jue Bang ◽  
Eric Van Cutsem ◽  
Charles S. Fuchs ◽  
Yelena Y. Janjigian ◽  
...  
Keyword(s):  
Adverse Events ◽  
Disease Progression ◽  
Performance Status ◽  
Gastroesophageal Junction ◽  
Locally Advanced ◽  
Treatment Withdrawal ◽  
First Line ◽  
Serious Adverse Events ◽  
End Points ◽  
Expression Status

TPS263 Background: For patients with unresectable, locally advanced recurrent or metastatic G/GEJ cancer, the standard of care includes a fluoropyrimidine plus a platinum-based agent as first-line therapy. The PD-1 inhibitor pembrolizumab has demonstrated durable antitumor activity in this patient population across lines of therapy. Herein, we describe the randomized, double-blind, phase 3 KEYNOTE-859 trial (NCT03675737) of first-line pembrolizumab plus chemotherapy in patients with advanced G/GEJ adenocarcinoma. Methods: Patients with histologically or cytologically confirmed, locally advanced unresectable or metastatic G/GEJ adenocarcinoma with known PD-L1 expression status, HER2-negative disease, measurable disease per RECIST v1.1, and ECOG performance status of 0 or 1 will be randomly assigned 1:1 to receive pembrolizumab plus chemotherapy or placebo plus chemotherapy. Randomization will be stratified by geographic region (Europe/Israel/North America/Australia vs Asia vs rest of world), PD-L1 tumor expression status (combined positive score < 1 vs ≥1), and combination chemotherapy (FP vs CAPOX). Pembrolizumab or placebo will be administered at 200 mg IV every 3 weeks (Q3W). The chemotherapy regimen will be investigator’s choice of FP (continuous infusion of 5-fluorouracil [800 mg/m2/day on days 1-5 of each cycle] plus IV cisplatin [80 mg/m2] Q3W) or CAPOX (oral capecitabine [1000 mg/m2 twice daily on days 1-14 of each cycle] plus IV oxaliplatin [130 mg/m2 on day 1 of each cycle] Q3W). Duration of cisplatin or oxaliplatin may be capped at 6 cycles per local country guidelines; treatment with 5-fluorouracil or capecitabine may continue per protocol. Treatment with pembrolizumab or placebo will continue for ≤35 administrations (~2 years) or until disease progression, unacceptable toxicity, intercurrent illness that prevents further administration of treatment, investigator decision, or noncompliance. Imaging will be performed at screening and subsequently every 6 weeks until disease progression, start of new anticancer treatment, withdrawal of consent, or death. Adverse events will be monitored throughout the study from the time of randomization to 30 days after the last dose of study treatment (90 days for serious adverse events). The dual primary end points are OS and PFS per RECIST v1.1 as assessed by blinded independent central review (BICR). Secondary end points include ORR and DOR per RECIST v1.1 as assessed by BICR, safety, and tolerability. Enrollment is ongoing. Clinical trial information: NCT03675737.

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