344 Phase 3 trial of pembrolizumab and enzalutamide versus enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) (KEYNOTE-641)

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A369-A369
Author(s):  
Julie Nicole Graff ◽  
Joseph Burgents ◽  
Li Wen Liang ◽  
Arnulf Stenzl
Keyword(s):  
Response Rate ◽  
Objective Response ◽  
Abiraterone Acetate ◽  
Phase 3 ◽  
Once Daily ◽  
Link Type ◽  
Phase 2 Study ◽  
Psa Response ◽  
Pretreated Patients ◽  
Modified Recist

BackgroundAntitumor activity with pembrolizumab + enzalutamide was observed in cohort C of the phase 1b/2 KEYNOTE-365 (NCT02861573) study of abiraterone acetate–pretreated patients with mCRPC and in a phase 2 study (NCT02312557) of patients with mCRPC who experienced progression with enzalutamide alone. In KEYNOTE-365 cohort C, prostate-specific antigen (PSA) response rate was 22%, objective response rate (ORR) was 20%, and 12-month PFS and OS rates were 24.6% and 72.8%, respectively. Safety and tolerability of the combination was consistent with individual profiles of each agent. In the phase 2 study of enzalutamide-pretreated patients, 5 of 28 patients (18%) had a PSA decline of ≥50%, and 3 of 12 patients (25%) with measurable disease achieved objective response. KEYNOTE-641 (NCT03834493) is a randomized, phase 3 trial to assess efficacy and safety of pembrolizumab + enzalutamide versus placebo + enzalutamide in patients with mCRPC.MethodsEnrolled patients have biochemical or radiographic progression with androgen deprivation therapy/after bilateral orchiectomy within 6 months of screening, ECOG PS 0/1, ongoing androgen deprivation with serum testosterone <50 ng/dL, and tumor tissue availability for biomarker analysis. The study continues to enroll those who previously had abiraterone acetate therapy; the abiraterone-naive cohort is filled. Exclusion criteria are prior chemotherapy for mCRPC, checkpoint inhibition, or any treatment with a second-generation androgen receptor inhibitor. Treatment stratification factors are prior abiraterone acetate treatment (yes or no), metastases location (bone only or liver or other), and prior docetaxel treatment for metastatic hormone-sensitive prostate cancer (yes or no). Response and progression will be determined by imaging (CT/MRI/bone) per PCWG3–modified RECIST v1.1 on visits Q9W during the first year and Q12W thereafter. Approximately 1200 adults will be randomly assigned 1:1 in a double-blind fashion to receive enzalutamide 160 mg orally once daily + pembrolizumab 200 mg IV Q3W or enzalutamide 160 mg orally once daily + placebo for a maximum of 35 cycles or until disease progression, unacceptable toxicity, or consent withdrawal. Coprimary end points are radiographic PFS per PCWG3-modified RECIST v1.1, as assessed by blinded independent central review, and OS. The key secondary end point is time to subsequent anticancer therapy or death. Other secondary end points are ORR, DOR, PSA response rate, PSA undetectable rate, time to PSA progression, time to pain progression, time to symptomatic skeletal-related event, time to soft tissue progression, and safety. KEYNOTE-641 is ongoing or planned in 21 countries across Asia, Australia, Europe, and North and South America.ResultsN/AConclusionsN/ATrial RegistrationClinicalTrials. gov, NCT03834493Ethics ApprovalThe study and the protocol were approved by the Institutional Review Board or ethics committee at each site.

343 Phase 3 study of pembrolizumab + docetaxel and prednisone/prednisolone for metastatic castration-resistant prostate cancer (mCRPC) pretreated with next-generation hormonal agents (NHAs) (KEYNOTE-921)

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A368-A368
Author(s):  
Daniel Petrylak ◽  
Neal Shore ◽  
Mostefa Bennamoun ◽  
Raffaele Ratta ◽  
Josep Piulats ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Disease Progression ◽  
Response Rate ◽  
Abiraterone Acetate ◽  
Prior Treatment ◽  
Phase 3 ◽  
End Points ◽  
Link Type ◽  
Psa Response ◽  
Modified Recist

BackgroundCohort B of the phase 1b/2 KEYNOTE-365 study (NCT02861573) found that docetaxel + pembrolizumab + prednisone demonstrated activity in patients previously treated with abiraterone acetate or enzalutamide for mCRPC. The prostate-specific antigen (PSA) response rate was 28%; objective response rate (ORR) was 18% (7 partial responses); duration of response (DOR) was 6.7 months; progression-free survival (PFS) was 8.3 months; overall survival (OS) was 20.4 months; and the 12-month PFS and OS rates were 24.0% and 75.8%, respectively. The safety and tolerability profile of this combination was consistent with the profiles of each individual agent. The KEYNOTE-921 (NCT03834506) phase 3 trial will evaluate efficacy and safety of pembrolizumab + docetaxel + prednisone/prednisolone in patients with mCRPC after prior treatment with NHA.MethodsEligible patients are adults with histologically or cytologically confirmed mCRPC who experience disease progression with androgen deprivation therapy (or after bilateral orchiectomy) within 6 months of screening and have Eastern Cooperative Oncology Group performance status 0/1. Other eligibility criteria are disease progression or intolerance to NHA in the metastatic hormone-sensitive prostate cancer setting or CRPC setting, no prior treatment with chemotherapy for mCRPC, and tissue available for biomarker analysis. Treatment stratification factors are prior treatment with abiraterone acetate (yes or no) and metastases location (bone only, liver, other). Approximately 1000 patients will be randomly assigned to receive docetaxel 75 mg/m2 IV Q3W + prednisone/prednisolone 5 mg orally BID and pembrolizumab 200 mg IV Q3W or docetaxel 75 mg/m2 IV Q3W + prednisone/prednisolone 5 mg PO BID + placebo IV Q3W (1:1 ratio). Response and progression will be determined using imaging (CT/MRI/bone) according to PCWG3–modified RECIST v1.1 by blinded independent central review (BICR) Q9W during the first year and Q12W thereafter. Treatment maximums are 10 cycles for docetaxel + prednisone/prednisolone and 35 cycles for pembrolizumab or placebo. Treatment discontinuation regardless of therapy received is mandated for disease progression, unacceptable toxicity, or consent withdrawal. The dual primary end points are radiographic PFS per PCWG3-modified RECIST v1.1, as assessed by BICR and OS, and the key secondary end point is time to initiation of subsequent anticancer therapy or death. Other secondary end points include PSA response rate, time to PSA progression, ORR, DOR, time to radiographic soft tissue progression, time to radiographic bone progression, and safety. KEYNOTE-921 is ongoing or planned in 22 countries across, Asia, Australia, Europe, and North and South America.ResultsN/AConclusionsN/AEthics ApprovalThe study and the protocol were approved by the Institutional Review Board or ethics committee at each site.

scholarly journals 345 Phase 3 study of combination pembrolizumab + olaparib therapy versus enzalutamide/abiraterone in metastatic castration-resistant prostate cancer (mCRPC) after progression on chemotherapy (KEYLYNK-010)

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A370-A370
Author(s):  
Evan Yu ◽  
Se Hoon Park ◽  
Yi-Hsiu Huang ◽  
Mostefa Bennamoun ◽  
Lu Xu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Homologous Recombination ◽  
Group Performance ◽  
Phase 3 ◽  
End Points ◽  
Link Type ◽  
Patient Reported ◽  
Pretreated Patients ◽  
Modified Recist ◽  
Docetaxel Chemotherapy

BackgroundCohort A of the phase 1b/2 KEYNOTE-365 study (NCT02861573) demonstrated promising antitumor activity with pembrolizumab + olaparib in patients with mCRPC unselected for homologous recombination deficiency. The prostate-specific antigen (PSA) and objective response rates (ORR) were both 9%, progression-free survival (PFS) was 4.3 months, overall survival (OS) was 14.4 months, and 12-month PFS and OS rates were 23.3% and 58.2%, respectively. The safety profile of the combination therapy was also aligned with the individual profiles of each agent. KEYLYNK-010 (NCT03834519) is a phase 3 trial to evaluate efficacy and safety of pembrolizumab + olaparib in molecularly unselected enzalutamide- or abiraterone-pretreated patients with mCRPC who progressed with docetaxel chemotherapy.MethodsEligibility criteria include histologically confirmed mCRPC unselected for homologous recombination repair (HRR) gene mutation, progression on docetaxel chemotherapy, progression on androgen deprivation therapy within 6 months before screening, received either abiraterone for metastatic castration-sensitive prostate cancer/mCRPC or enzalutamide for mCRPC (but not both) for ≥8 weeks (≥14 weeks with bone progression), and Eastern Cooperative Oncology Group performance status of 0 or 1. Patients will also be required to provide tumor tissue for biomarker analysis. Approximately 780 adults will be randomized in a 2:1 ratio to pembrolizumab 200 mg IV Q3W (maximum 35 cycles) + olaparib 300 mg PO QD or abiraterone 1000 mg PO QD + prednisone or prednisolone 5 mg PO BID (enzalutamide-pretreated patients) or enzalutamide 160 mg PO QD (abiraterone-pretreated patients). Randomization will be stratified by prior treatment (abiraterone or enzalutamide) and measurable disease (yes/no). Treatment for all patients will continue until disease progression, unacceptable toxicity, or withdrawal. Response will be assessed by imaging (CT/MRI/bone) per Prostate Cancer Working Group 3 (PCWG3)–modified RECIST v1.1 by blinded independent central review (BICR) Q9W during the first year and then Q12W thereafter. The dual primary end points are radiographic PFS per PCWG3-modified RECIST v1.1, as assessed by BICR and OS. The key secondary end point is time to initiation of subsequent anticancer therapy or death. Other secondary end points include ORR, duration of response, time to PSA progression, time to first symptomatic skeletal-related event, and safety and tolerability. Patient-reported outcomes and identification of molecular biomarkers for treatment response are exploratory end points. KEYLYNK-010 is ongoing or planned in 19 countries across Asia, Australia, Europe, and North and South America.ResultsN/AConclusionsN/ATrial RegistrationClinicalTrials. gov, NCT03834519Ethics ApprovalThe study and the protocol were approved by the Institutional Review Board or ethics committee at each site.

scholarly journals 347 KEYNOTE-365 cohort C: pembrolizumab + enzalutamide in patients with abiraterone acetate–pretreated metastatic castration-resistant prostate cancer (mCRPC)—data after minimum of 22 months of follow-up

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A374-A374
Author(s):  
Leonard Appleman ◽  
Tilman Todenhoefer ◽  
William Berry ◽  
Howard Gurney ◽  
Margitta Retz ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Response Rate ◽  
Abiraterone Acetate ◽  
End Points ◽  
Link Type ◽  
Measurable Disease ◽  
Psa Response ◽  
Psa Progression ◽  
Grade 3

BackgroundPrevious data from cohort C of phase 1b/2 study KEYNOTE-365 (NCT02861573) showed that PD-1 inhibitor pembrolizumab + enzalutamide was well tolerated and showed antitumor activity in patients with abiraterone acetate–pretreated mCRPC. Updated data after a minimum of 22 months of follow-up are presented.MethodsPatients in the prechemotherapy mCRPC state who were intolerant to ≥4 weeks‘ treatment with abiraterone acetate or for whom this treatment failed, had progressive disease ≤6 months before screening, and had ECOG PS 0-2 were enrolled. Patients received pembrolizumab 200 mg IV Q3W + enzalutamide 160 mg orally QD. Primary end points were PSA response rate (decrease ≥50% from baseline), confirmed ORR per RECIST v1.1 by blinded independent central review (BICR), and safety. Secondary end points were time to PSA progression; DCR (CR or PR of any duration + SD or non-CR/non-PD ≥6 months) and DOR per RECIST v1.1 by BICR; rPFS per PCWG3-modified RECIST v1.1 by BICR; and OS.ResultsOf 103 enrolled patients, 102 were treated. Median age was 70.0 years (range, 43–87); 29.4% of patients were PD-L1+; 37.3% had RECIST-measurable disease. Median follow-up (time from enrollment to data cutoff) was 40.2 months (range, 22.3–49.9). Confirmed PSA response rate in patients with baseline PSA measurement (N = 101) was 23.8%. Median time to PSA progression was 4.0 months (95% CI, 3.5–4.4). In 38 patients with measurable disease, ORR was 10.5% (2 CR; 2 PR). Median DOR was 11.8 months (4.3 to 38.3+ months); 1 patient had a response ≥12 months. DCR for the total population was 33.3%. Median (95% CI) rPFS was 6.0 months (4.1–6.3); rPFS at 12 months was 30.1%. Median (95% CI) OS was 20.1 months (16.9–25.2); OS at 12 months was 76.2%. Treatment-related AEs (TRAEs) occurred in 92.2% of patients; most common (≥20%) were fatigue (39.2%), nausea (21.6%), and rash (21.6%). Grade 3–5 TRAEs occurred in 42.2%, most commonly rash (7.8%) and fatigue (5.9%). Four patients died of AEs: 1 death was treatment-related (unknown cause).ConclusionsAfter a minimum follow-up of 22 months, pembrolizumab + enzalutamide continued to show antitumor activity in abiraterone acetate–pretreated mCRPC. The safety profile of pembrolizumab + enzalutamide was generally consistent with individual profiles of each agent. There was a higher incidence than typically reported for the individual agents of all-grade (21.6%) and grade 3 (7.8%) rash, which resolved with standard-of-care treatment. The combination is being further evaluated in the phase 3 study KEYNOTE-641.AcknowledgementsMedical writing and/or editorial assistance was provided by Matthew Grzywacz, PhD, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.Trial RegistrationClinicalTrialsgov, identifier: NCT02861573Ethics ApprovalThe study and the protocol were approved by the Institutional Review Board or ethics committee at each site.

346 KEYNOTE-991: phase 3 study of pembrolizumab plus enzalutamide and androgen deprivation therapy (ADT) for patients with metastatic hormone-sensitive prostate cancer (mHSPC)

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A371-A371
Author(s):  
Christian Gratzke ◽  
Christian Gratzke ◽  
Christian Gratzke ◽  
Cuizhen Niu ◽  
Christian Poehlein ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Antitumor Activity ◽  
The United States ◽  
Phase 3 ◽  
End Points ◽  
Once Daily ◽  
Link Type ◽  
Patient Reported ◽  
Biomarker Analysis ◽  
Modified Recist

BackgroundCombination of pembrolizumab, an anti–PD-1 antibody, added to enzalutamide, a nonsteroidal antiandrogen agent, has shown antitumor activity in abiraterone-resistant mCRPC (KEYNOTE-365, NCT02861573) and in patients with mCRPC for whom enzalutamide was ineffective (KEYNOTE-199, NCT02787005). These data indicate that the combination of pembrolizumab + enzalutamide with ADT warrants phase 3 evaluation. Also, efficacy in enzalutamide may be proimmunogenic, suggesting that it may be additive or synergistic in antitumor activity when combined with pembrolizumab.MethodsThe KEYNOTE-991 (NCT04191096) phase 3 trial will evaluate the efficacy and safety of enzalutamide + ADT (LHRH agonist/antagonist during study treatment or bilateral orchiectomy) + pembrolizumab or placebo in patients with mHSPC. Eligibility criteria include age ≥18 years, mHSPC, ≥2 bone lesions or visceral disease, no prior treatment with next-generation hormone agents, adequate organ function, and ECOG PS 0 or 1. Patients must provide tissue for biomarker analysis. Approximately 1232 patients will be randomized in a 1:1 ratio to receive enzalutamide 160 mg orally once daily + ADT + pembrolizumab 200 mg IV every 3 weeks (Q3W) or enzalutamide 160 mg orally once daily + ADT + placebo IV Q3W. Treatment will continue with pembrolizumab up to 35 cycles and treatment with enzalutamide will proceed continuously from day 1 of cycle 1 until disease progression, unacceptable toxicity, or withdrawal of consent. The stratification factors are prior docetaxel therapy (yes or no) and presence of high-volume disease (yes or no). CT or MRI and radionuclide bone imaging will be used to assess response according to Prostate Cancer Working Group 3 (PCWG3)–modified RECIST v1.1 by blinded independent central review (BICR) Q12W from the date of randomization. Imaging will continue until the end of treatment and will resume Q12W during the posttreatment period. The co-primary end points are BICR-assessed radiographic PFS (according to PCWG3-modified RECIST v1.1) and OS. Key secondary end points are time to first subsequent anticancer therapy and time to symptomatic skeletal-related event. Other end points are PFS2 (progression after next line of therapy or death), PSA response rate, time to PSA progression, PSA undetectable rate, ORR, duration of response, time to soft tissue and radiographic bone progression per PCWG3-modified RECIST v1.1, safety, and patient-reported outcomes (eg, time to pain progression). Safety and tolerability will be evaluated using a tiered approach. KEYNOTE-991 is enrolling at 40 sites in Australia, Chile, Colombia, Israel, Japan, Poland, South Korea, Spain, Switzerland, Taiwan, and the United States.ResultsN/AConclusionsN/ATrial RegistrationClinicalTrials. gov: NCT04191096Ethics ApprovalThe study and the protocol were approved by the Institutional Review Board or ethics committee at each site.

scholarly journals 417 Phase 3 study of pembrolizumab + belzutifan + lenvatinib or pembrolizumab/quavonlimab + lenvatinib versus pembrolizumab + lenvatinib as first-line treatment for advanced renal cell carcinoma

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A447-A447
Author(s):  
Toni Choueiri ◽  
Elizabeth Plimack ◽  
Thomas Powles ◽  
Martin Voss ◽  
Howard Gurney ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Antitumor Activity ◽  
Line Treatment ◽  
First Line ◽  
Phase 3 ◽  
End Points ◽  
Once Daily ◽  
Link Type ◽  
The World ◽  
First Line Treatment

BackgroundPembrolizumab + vascular endothelial growth factor (VEGF) inhibitor lenvatinib demonstrated antitumor activity as first-line treatment for advanced clear cell renal cell carcinoma (ccRCC) in phase 3 trial KEYNOTE-581/CLEAR (NCT02811861). Hypoxia-inducible factor 2α (HIF-2α) inhibitor belzutifan (MK-6482) showed antitumor activity in ccRCC, and a coformulation of pembrolizumab and CTLA-4 inhibitor quavonlimab (MK-1308A) showed antitumor activity in non–small cell lung cancer. HIF-2α or CTLA-4 inhibition with PD-1 and VEGF inhibition backbone combination may provide additional benefit as first-line treatment in ccRCC. This open-label, randomized, phase 3 study (NCT04736706) will be conducted to compare novel combination therapies pembrolizumab + belzutifan + lenvatinib (arm A) and MK-1308A + lenvatinib (arm B) with pembrolizumab + lenvatinib (arm C).MethodsApproximately 1431 adults with metastatic ccRCC, measurable disease per RECIST v1.1, and Karnofsky Performance Status Scale score ≥70% who had not previously undergone systemic therapy for advanced ccRCC will be enrolled. Patients will be randomly assigned 1:1:1 to arm A (belzutifan 120 mg + lenvatinib 20 mg oral once daily + pembrolizumab 400 mg IV every 6 weeks), arm B (MK-1308A [quavonlimab 25 mg + pembrolizumab 400 mg] IV every 6 weeks and lenvatinib 20 mg oral once daily), or arm C (pembrolizumab 400 mg IV every 6 weeks + lenvatinib 20 mg oral once daily). Treatment will continue until documented disease progression, withdrawal of consent, or other discontinuation event; patients will receive pembrolizumab and MK-1308A for up to 18 cycles (approximately 2 years). Patients will be stratified by International mRCC Database Consortium (IMDC) score (favorable vs intermediate vs poor), region of the world (North America vs Western Europe vs rest of the world), and sarcomatoid features (yes vs no). Response will be assessed by CT or MRI per RECIST v1.1 by blinded independent central review (BICR) at week 12 from randomization, every 6 weeks through week 78, and every 12 weeks thereafter. Adverse events and serious adverse events will be monitored throughout the study and for 90 days after treatment. Dual primary end points are progression-free survival per RECIST v1.1 by BICR and overall survival. Primary end points will be assessed in arm A compared with arm C and in arm B compared with arm C for patients with IMDC intermediate/poor status and in all patients regardless of IMDC status. Secondary end points are objective response rate and duration of response per RECIST v1.1 by BICR, patient-reported outcomes, and safety.AcknowledgementsMedical writing and/or editorial assistance was provided by Matthew Grzywacz, PhD, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Eisai Inc., Woodcliff Lake, NJ, USA. Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA,Eisai Inc., Woodcliff Lake, NJ, USA.Trial RegistrationClinicaltrials.gov, NCT04736706Ethics ApprovalThe study and the protocol were approved by the Institutional Review Board or ethics committee at each site.

scholarly journals Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with human papillomavirus-associated malignancies

2020 ◽  
Vol 8 (2) ◽  
pp. e001395
Author(s):  
Julius Strauss ◽  
Margaret E Gatti-Mays ◽  
Byoung Chul Cho ◽  
Andrew Hill ◽  
Sébastien Salas ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
Fusion Protein ◽  
Response Rate ◽  
Checkpoint Inhibitor ◽  
Phase 1 ◽  
Objective Response ◽  
Additional Patient ◽  
Phase 2 ◽  
Link Type ◽  
Bifunctional Fusion Protein

BackgroundBintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of transforming growth factor (TGF)-βRII (a TGF-β ‘trap’) fused to a human IgG1 mAb blocking programmed cell death ligand 1. This is the largest analysis of patients with advanced, pretreated human papillomavirus (HPV)-associated malignancies treated with bintrafusp alfa.MethodsIn these phase 1 (NCT02517398) and phase 2 trials (NCT03427411), 59 patients with advanced, pretreated, checkpoint inhibitor-naive HPV-associated cancers received bintrafusp alfa intravenously every 2 weeks until progressive disease, unacceptable toxicity, or withdrawal. Primary endpoint was best overall response per Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1; other endpoints included safety.ResultsAs of April 17, 2019 (phase 1), and October 4, 2019 (phase 2), the confirmed objective response rate per RECIST V.1.1 in the checkpoint inhibitor-naive, full-analysis population was 30.5% (95% CI, 19.2% to 43.9%; five complete responses); eight patients had stable disease (disease control rate, 44.1% (95% CI, 31.2% to 57.6%)). In addition, three patients experienced a delayed partial response after initial disease progression, for a total clinical response rate of 35.6% (95% CI, 23.6% to 49.1%). An additional patient with vulvar cancer had an unconfirmed response. Forty-nine patients (83.1%) experienced treatment-related adverse events, which were grade 3/4 in 16 patients (27.1%). No treatment-related deaths occurred.ConclusionBintrafusp alfa showed clinical activity and manageable safety and is a promising treatment in HPV-associated cancers. These findings support further investigation of bintrafusp alfa in patients with advanced, pretreated HPV-associated cancers.

Phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naive patients and patients pretreated with fluorouracil-based chemotherapy.

1997 ◽  
Vol 15 (1) ◽  
pp. 251-260 ◽  
Author(s):  
P Rougier ◽  
R Bugat ◽  
J Y Douillard ◽  
S Culine ◽  
E Suc ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Adverse Events ◽  
Metastatic Colorectal Cancer ◽  
Advanced Colorectal Cancer ◽  
Response Rate ◽  
Objective Response ◽  
World Health ◽  
Who Grade ◽  
Pretreated Patients ◽  
Grade 3

PURPOSE To assess the efficacy of irinotecan (CPT-11) in the treatment of advanced colorectal cancer in both chemotherapy-naive and pretreated patients. PATIENTS AND METHODS Two hundred thirteen patients (aged 18 to 75 years) with metastatic colorectal cancer, World Health Organization (WHO) performance status < or = 2, and life expectancy > or = 3 months were treated with CPT-11 350 mg/m2 every 3 weeks. All 178 patients eligible for efficacy analysis had not received more than one prior fluorouracil (5-FU)-based chemotherapy regimen (adjuvant or palliative) and had adequate hematologic, renal, and hepatic function. RESULTS Primary tumor sites were the colon (71%) and rectum (28%). Sixty-six percent of the patients had > or = two metastatic sites. Ninety-eight percent of the patients had undergone previous surgery, and 77.5% had received prior chemotherapy. Thirty-two of 178 eligible patients achieved on objective response (four complete responses [CRs] and 28 partial responses [PRs]; response rate, 18%; 95% confidence interval, 12.6% to 24.4%), 65 were stable, and 59 progressed. The response rate was 17.7% in the pretreated group and 18.8% in the chemotherapy-naive group. Within the former subgroup, response rates of 16.1% were reported in patients who were progressive on prior 5-FU chemotherapy and 19.1% in patients who were progressive off such treatment. The median duration of objective response (9.1 months) and median time to achievement of a response (9.3 weeks) did not differ between chemotherapy-naive and pretreated patients. The most frequent adverse events were neutropenia, which developed in 80% of the patients, delayed diarrhea (87%), alopecia (88%), fatigue (81%), and nausea/vomiting (77%). All these adverse events were manageable. Severe (WHO grade 3 or 4) neutropenia was only observed in 18% of the cycles, leukopenia in 11%, delayed diarrhea in 11%, and nausea and vomiting in 3%. Development of simultaneous grade 3 or 4 neutropenia and delayed diarrhea during 4% of the cycles was the safety issue of greatest concern. CONCLUSION CPT-11 has definite activity in the treatment of advanced metastatic colorectal cancer both in chemotherapy-naive and in pretreated patients who experienced disease progression on 5-FU, which suggests a lack of cross-resistance between CPT-11 and 5-FU. Diarrhea and neutropenia, the major toxicities of CPT-11, contribute to the risk to develop febrile neutropenic sepsis.

Randomized phase II trial of docetaxel, with or without doxercalciferol, in advanced, androgen-independent prostate cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5119-5119
Author(s):  
S. Attia ◽  
J. Eickhoff ◽  
G. Wilding ◽  
J. Blank ◽  
H. Rezazadeh ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Vitamin D ◽  
Response Rate ◽  
Performance Status ◽  
Single Agent ◽  
Objective Response ◽  
Double Blind ◽  
Vitamin D Analogs ◽  
Psa Response ◽  
Androgen Independent

5119 Background: Docetaxel is the standard of care for advanced androgen-independent prostate cancer (AIPC). Doxercalciferol, a vitamin D analog (1a-hydroxyvitamin D2), has single-agent activity in AIPC (Clin Cancer Res 9(11), 2003). Preclinical evidence supports combining vitamin D with chemotherapy to treat AIPC. Here we report results of a multi-institutional trial combining docetaxel and doxercalciferol. Methods: Patients with chemo-naive AIPC were randomized 1:1 to receive, on a four week cycle, docetaxel (35 mg/m2 IV; days 1, 8 and 15) with either doxercalciferol (10 mcg PO daily, days 1–28) or placebo in a double-blind fashion. The primary endpoint was to compare progression-free survival (PFS). Secondary endpoints were to assess overall survival (OS), objective response (RECIST), PSA response (consensus criteria), and toxicity. PFS and OS were analyzed on an intent-to-treat basis. Eligibility criteria included no prior cytotoxic therapy; radiographic evidence of metastasis; performance status ≤ 2 and no recent history of nephrolithiasis. Results: Seventy patients were randomized. Median follow-up time was 16.2 months (range, 0–40.5 months). Median PFS in the doxercalciferol arm was 14.9 months (95% CI: 8.7–16.6 months) versus 11.9 months (95% CI: 8.9–16.4 months) in the placebo arm (p=0.73). Median OS in the doxercalciferol arm was 18.1 months (95% CI: 14.9–26.2 months) and 17.9 months (95% CI: 12.1–24.6 months) in the placebo arm (p=0.63). Twenty-nine patients in the doxercalciferol arm and 33 in the placebo arm were evaluable for objective response. No complete responses were seen. Partial response rate was 14% (doxercalciferol) vs. 15% (placebo) (p=0.88). PSA response rate was 44% (95% CI: 29%-60%) in the doxercalciferol arm and 42% (95% CI: 27%-59%) in the placebo arm (p=0.87). Grade 3/4 toxicity rates were 38% in the doxercalciferol arm and 39% in the placebo arm (p=0.99). Conclusions: Despite encouraging data with other vitamin D analogs combined with docetaxel in AIPC, the addition of daily doxercalciferol to weekly docetaxel did not enhance median PFS, OS or tumor response. Toxicity was similar between treatment groups. Further evaluation of vitamin D analogs in combination with chemotherapy in AIPC remains of interest. No significant financial relationships to disclose.

First-line (1L) avelumab treatment in patients (pts) with metastatic Merkel cell carcinoma (mMCC): Preliminary data from an ongoing study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9530-9530 ◽  
Author(s):  
Sandra P. D'Angelo ◽  
Jeffrey Russell ◽  
Jessica Cecile Hassel ◽  
Celeste Lebbe ◽  
Bartosz Chmielowski ◽  
...  
Keyword(s):  
Safety Profile ◽  
Response Rate ◽  
Objective Response ◽  
Durable Response ◽  
Phase 2 Study ◽  
Grade 3 ◽  
Related Reaction ◽  
Unacceptable Toxicity ◽  
Clinical Trial Information

9530 Background: MCC is a rare, aggressive skin cancer. Avelumab is a fully human anti–PD-L1 antibody. In a phase 2 study in pts with distant mMCC who progressed after prior chemotherapy (JAVELIN Merkel 200; NCT02155647), avelumab showed a manageable safety profile and durable responses, including an objective response rate (ORR) of 31.8%, estimated 6-month durable response rate of 29%, and 6-month overall survival rate of 69%. Here, we report preliminary results from a separate cohort of pts with chemotherapy-naïve mMCC enrolled in the same study. Methods: Eligible pts with mMCC and no prior systemic treatment for metastatic disease received avelumab 10 mg/kg Q2W until confirmed progression, unacceptable toxicity, or withdrawal. Tumors were assessed every 6 weeks (RECIST v1.1). Adverse events (AEs) were assessed by NCI CTCAE v4.0. Results: As of Dec 30, 2016, 29/112 planned pts had been enrolled. Median age was 75.0 years (range 47–87). Median treatment duration was 8.1 weeks (range 2.0–37.9). Of 16 pts with ≥3 months of follow-up, unconfirmed ORR was 68.8% (95% CI 41.3–89.0) with CR in 18.8%; confirmed ORR was 56.3% (95% CI 29.9–80.2; 1 unconfirmed PR with discontinuation). Of 25 pts with ≥6 weeks of follow-up, unconfirmed ORR was 64.0% (95% CI 42.5–82.0). All responses were ongoing at last follow-up, including in 5/5 pts with ≥6 months of follow-up (potential to confirm responses). 20/29 pts (69.0%) had a treatment-related AE (TRAE), including grade 3–4 TRAE in 5 pts (17.2%). TRAEs led to discontinuation in 5 pts (17.2%): 2 pts with infusion-related reaction, and 1 pt each with elevated AST and ALT, cholangitis, and paraneoplastic syndrome. There were no treatment-related deaths. 21/29 pts (72.4%) remain on treatment. Conclusions: In initial results from a cohort of chemotherapy-naïve pts with mMCC, avelumab was associated with early responses and a manageable safety profile, consistent with findings for second-line or later avelumab treatment in a previous cohort. These results suggest that responses mature to become durable and the use of 1L avelumab may increase the probability of response vs later-line treatment. Enrollment and follow-up in this 1L cohort are ongoing. Clinical trial information: NCT02155647.

Abiraterone acetate plus prednisone (AA+P) without continuing LHRH-therapy in patients with metastatic chemotherapy: Naive castrations-resistant prostate cancer—Results from the SPARE-trial (NCT02077634).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5046-5046 ◽  
Author(s):  
Carsten Henning Ohlmann ◽  
Christoph Ruessel ◽  
Roger Zillmann ◽  
Eva Hellmis ◽  
Henrik Suttmann ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Objective Response ◽  
Serum Testosterone ◽  
Abiraterone Acetate ◽  
Castration Resistant Prostate Cancer ◽  
Testosterone Levels ◽  
Psa Response ◽  
Secondary Endpoints ◽  
Psa Progression ◽  
Lhrh Therapy

5046 Background: The value of continuation of androgen deprivation therapy (ADT) in metastatic castration-resistant prostate cancer (CRPC) remains controversial and clear evidence is lacking. Especially upon treatment with the life-prolonging cytochrome P450 17-alpha-hydroxylase/C17,20 lyase (Cyp17)-inhibitor, abiraterone acetate (AA), which in combination with prednisone (P), has the ability to further suppress serum testosterone levels over ADT alone, continuation of ADT seems to be negligible. Methods: The exploratory phase II trial randomized CRPC patients to receive continued ADT plus AA+P versus AA+P alone (NCT02077634), funded by Jansen-Cilag GmbH, Germany. The primary endpoint was rate of rPFS at month 12, not powered for a direct comparison between treatment arms. Secondary endpoints included PSA response rate, objective response, time to PSA progression and safety. Results: Altogether, 67 patients were randomized between 08/2014 to 04/2017. Median testosterone-levels (T) remained far below castrate-levels throughout treatment in all patients. However, in 6 patients (18%) from Arm B, T-levels increased above castrate levels within 28 days after cessation of AA+P treatment. Median treatment duration is shorter in Arm A. Safety analysis is underway and results will be presented. Conclusions: Results of this exploratory study suggest that treatment with AA+P without ADT may be effective in patients with mCRPC and that ADT may not be necessary in patients receiving AA+P. In some patients, serum-testosterone levels may rise rapidly upon treatment discontinuation so that the levels should be monitored closely. Clinical trial information: NCT02077634. [Table: see text]

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