bluuebunny/crossref_metadata_2025 huggingface dataset:
A randomized, phase II efficacy assessment of multiple MET kinase inhibitors in metastatic papillary renal carcinoma (PRCC): SWOG S1500.
Authors: Pal Sumanta K. , Tangen Catherine M. , Thompson Ian Murchie , Shuch Brian M. , Haas Naomi B. , George Daniel J. , Stein Mark N. , Wright John Joseph , Plets Melissa , Lara Primo
Published: September 2018

TPS4599

Background: PRCC constitutes approximately 15% of RCC cases, and no standard of care exists for metastatic disease. Approved VEGF- and mTOR-directed therapies for clear cell RCC in metastatic PRCC (mPRCC) have generally been ineffective. Trials assessing sunitinib and everolimus in non-clear cell RCC show a numerical advantage in progression-free survival (PFS) with sunitinib therapy. Prospective studies evaluating sunitinib in mPRCC show a broad range of efficacy, with PFS ranging from 1.6-6.6 months. Another possible approach to treating mPRCC is to target the MET protooncogene, which is frequently altered across both type I and type II disease. SWOG 1500 is a randomized, phase II study which will compare sunitinib to three MET-directed therapies in pts with mPRCC. Methods: Eligible pts will have PRCC (type I, type II or NOS), Zubrod performance status 0-1, and measurable metastatic disease. Pts may have received up to 1 prior systemic therapy, with the exception of prior VEGF-directed treatments. Treated brain metastases are allowed. Tissue must be available for central pathologic review of papillary subtype. Pts will receive either oral sunitinib, cabozantinib, crizotinib or savolitinib in a 1:1:1:1 randomization, with stratification by (1) prior therapy (0 vs 1) and (2) PRCC subtype (type I vs type II vs NOS). The primary endpoint of the study is to compare PFS with sunitinib to PFS with MET-directed therapies. Secondary endpoints in the study include comparison of response rate, overall survival and safety profile. Translational aims of the study include correlation of clinical outcome with MET mutation, copy number and other markers of MET signaling. Radiographic assessment will be performed every 12 wks. Interim analyses are planned for each arm. A total of 275 pts will be enrolled, with 26 pts registered as of Jan 30, 2017. Clinical trial information: NCT02761057.
A randomized phase II study of chemoradiation and pembrolizumab for locally advanced cervical cancer.
Authors: Duska Linda R. , Showalter Timothy Norman , Petroni Gina R. , Bullock Timothy
Published: September 2018

TPS5601

Background: The standard of care for patients with LACC is concurrent chemoradiation therapy (CRT) with weekly cisplatin. Five-year disease overall survival after contemporary CRT for LACC is only 66%. Human Papillomavirus (HPV) DNA is detected in virtually all cervical cancers, and HPV specific CD4+ helper and CD8+ cytotoxic T cells are found in cervical tumors, indicating the inherent immunogenicity of these tumors. The failure of the immune system to eradicate HPV DNA integration is thought to be associated with the cancer cells’ acquisition of mechanisms to avoid cytotoxic T cells, including, but not limited to, the expression of checkpoint inhibitory molecules such as PD-L1 and the recruitment of FoxP3+ immunosuppressive regulatory T cells. Low ratios of CD8+ T cells: regulatory T cells are associated with poor survival for cervical cancer patients, suggesting that strategies to enhance immune response would be effective. Additionally, in cervical cancer, PD-1 is expressed by the majority of infiltrating CD8+ T cells, suggesting that blocking of PD-1 could have therapeutic potential, inducing tumor-specific immunity in cervical cancer patients. We hypothesized that CRT may increase tumor responsiveness to anti-PD-1 therapy by enhancing antigen availability and disrupting immune-regulatory networks. However, it is unclear how treatment with cisplatin and/or ionizing radiation could influence the quality and quantity of the immune response. Methods: A randomized Phase II open-label multi-center study was designed in which 88 eligible subjects with LACC will be treated with standard CRT plus the PD-1 monoclonal antibody pembrolizumab. The primary objectives in the study are to estimate the safety and immune response to pembrolizumab given either sequentially or concurrently with CRT. Secondary objectives will evaluate the metabolic response and rates of distant metastases following treatment with pembrolizumab given sequentially or concurrently with CRT. The study design also affords the opportunity to characterize the effect of treatment on immune response pathways by estimating the effects of treatment on specific immune markers. Clinical trial information: NCT02635360.
TRUST: Trial of radical upfront surgical therapy in advanced ovarian cancer (ENGOT ov33 / AGO‐OVAR OP7).
Authors: Mahner Sven , Heitz Florian , Burges Alexander , Reuss Alexander , Kraemer Bernhard , Schmalfeldt Barbara , Sehouli Jalid , Lampe Bjoern , Schnelzer Andreas , Wimberger Pauline , Fotopoulou Christina , Guyon Frederic , Lecuru Fabrice , Querleu Denis , Greggi Stefano , Colombo Nicoletta , Aletti Giovanni Damiano , Harter Philipp , Du Bois Andreas
Published: September 2018

TPS5602

Background: Primary cytoreductive surgery (PDS) followed by chemotherapy has been considered as standard management for advanced ovarian cancer patients (pts) over decades. An alternative approach of interval debulking surgery (IDS) following neoadjuvant chemotherapy (NACT) was subsequently reported by two randomized phase III trials (EORTC‐GCG, CHORUS). Owing to important limitations of these studies, especially regarding surgical quality, optimal timing of surgical therapy in advanced ovarian cancer is still unclear. Methods: TRUST is an international open, randomized, controlled multicenter trial investigating overall survival (OS; primary endpoint) after PDS vs NACT and subsequent IDS in pts with FIGO stage IIIB‐IVB ovarian, tubal, and peritoneal carcinoma. Secondary objectives are safety of complete tumor resection, progression‐free survival and quality of life (QoL) as well as surgical morbidity. In order to guarantee adequate surgical quality, participating centers need to fulfill specific quality assurance criteria (e.g. ≥50% complete resection rate in upfront surgery for FIGO IIIB-IV pts, ≥36 debulking-surgeries/year) and agree to independent audits by TRUST Quality committee delegates. A 1:1 randomization to PDS or NACT followed by IDS stratified by center and age‐ECOG combination (ECOG 0 and age ≤65 years vs ECOG > 0 or age > 65 years) is performed. Pts in the PDS arm will undergo surgery followed by 6 cycles of platinum-based chemotherapy, whereas pts in the IDS arm will be treated with 3 cycles of NACT after histologic confirmation of the disease, followed by IDS and subsequently 3 cycles of platinum-based chemotherapy. Intention of surgery for both groups will be complete tumor resection as per guideline recommendations. Health related QoL will be assessed using the EORTC QLQ‐C30, QLQ‐OV28, and EQ‐5D‐3L questionnaires. For sample size planning, we considered a prolongation of median OS from 45 months in the IDS arm to 60 months in the PDS arm (HR 0.75) as clinically relevant. 380 events are needed to obtain a power of 80% in two‐sided log-rank test with significance level of 0.05. The primary analysis will be done in the ITT‐population of 686 randomized pts. By Feb 3 2017, 46 pts were randomized. Clinical trial information: NCT02828618.
FORWARD I (GOG 3011): A randomized phase 3 study to evaluate the safety and efficacy of mirvetuximab soravtansine (IMGN853) versus chemotherapy in adults with folate receptor alpha (FRα)-positive, platinum-resistant epithelial ovarian cancer (EOC), primary peritoneal cancer, or primary fallopian tube cancer.
Authors: Moore Kathleen N. , Vergote Ignace , Oaknin Ana , Colombo Nicoletta , Banerjee Susana N. , Oza Amit M. , Pautier Patricia , Kelly Catherine Margaret , Malek Karim S. , Ruiz-Soto Rodrigo , Birrer Michael J.
Published: September 2018

TPS5607

Background: Elevated FRα expression is characteristic of a number of solid tumors, including EOC, thereby providing an attractive candidate for targeted therapeutic approaches. Mirvetuximab soravtansine is an antibody-drug conjugate (ADC), comprising a FRα-binding antibody linked to the tubulin-disrupting maytansinoid DM4, that has shown single agent clinical activity and a favorable safety profile in an ongoing, first-in-human phase 1 trial (NCT01609556). Methods: FORWARD I is a randomized phase 3 study designed to evaluate the efficacy of mirvetuximab soravtansine compared with that of standard-of-care chemotherapy in adult patients with platinum-resistant EOC, primary peritoneal cancer, or fallopian tube cancer. Confirmation of FRα positivity by immunohistochemistry (medium or high expression; ≥ 50% of cells with at least moderate staining intensity) and ≤ 3 prior lines of therapy are required for inclusion. A maximum of 333 patients are expected to be recruited. Patients will be randomized 2:1 to Arm 1 (intravenous mirvetuximab soravtansine at a dose of 6.0 mg/kg, calculated using adjusted ideal body weight, on Day 1 of a 21-day cycle) or Arm 2 (investigators’ choice chemotherapy: paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary efficacy endpoint is progression-free survival (PFS; by blinded independent central review) and secondary endpoints include objective response rate, quality of life, overall survival, safety and tolerability, and duration of response. The first patient was enrolled in January 2017. Clinical trial information: NCT02631876.
Phase II open-label randomized multi-centre study of neoadjuvant olaparib in patients (pts) with platinum sensitive (PS) relapsed high grade serous ovarian cancer (OC): The NEO trial.
Authors: Kanjanapan Yada , Lheureux Stephanie , May Taymaa , Wilson Michelle K. , Bernardini Marcus , Shaw Patricia Ann , Vergote Ignace , Brenton James D. , Provencher Diane M. , McNeish Iain A. , Ghatage Prafull , Ledermann Jonathan A. , Colombo Nicoletta , Gourley Charlie , Weberpals Johanne , Ramsahai Janelle , Ricker Nicole , Accardi Sarah , Wang Lisa , Oza Amit M.
Published: September 2018

TPS5608

Background: Olaparib is a PARP inhibitor with clinical benefit in relapsed OC, especially in pts with germline BRCA1/2 mutation ( gBRCA). Study 19 (NCT00753545) found a progression free survival (PFS) gain from maintenance olaparib, post chemotherapy for PS relapse. Olaparib treatment in gBRCA OC pts relapsing post ≥ 3 prior chemotherapy regimens gave a response rate (RR) of 46% in the PS subgroup (Study 42; NCT01078662). Efficacy of olaparib may extend to OC with homologous recombination DNA repair pathway deficiency (HRD); susceptible to synthetic lethality from PARP inhibition. NEO [NCT02489006] is a window of opportunity study to assess tumor heterogeneity and the pharmacodynamic effects of olaparib given prior to surgery in PS OC, analyse the tumor genomic landscape pre and post olaparib, and assess for predictive biomarkers beyond BRCA mutation. Methods: This phase 2 study enrols pts with high grade serous OC, primary peritoneal or fallopian tube cancer with a progression free interval of ≥6 months and sensitive to their last line of platinum therapy. Pts must be suitable for secondary debulking surgery and agree to pre-operative tumour biopsy. All pts receive olaparib tablets 300mg po bid for 6 ± 2 weeks pre-surgery. Post-operatively, pts are randomised 1:1 to olaparib or 6 cycles of platinum-based chemotherapy followed by maintenance olaparib. The primary endpoint is the degree of PAR and PARP-1 inhibition in the blood and tumor following pre-operative olaparib in PS relapsed OC. Clinical efficacy is assessed by RR (RECIST 1.1), CA125, PFS and PFS2. Translational studies include next generation sequencing HRD panel to assess for somatic and germline mutations including RAD51B/C/D, PPM1D, FANCM, BRIP1, PALB2 and BARD1; evaluation of gene expression change in tumor tissue pre and post olaparib; assessment for resistance mechanisms and impact of heterogeneity. Circulating tumor DNA measured weekly pre-surgery is assessed for its prognostic value, alone and compared with CA125. The study will enrol 50-70 pts with estimated accrual of 3 pts/month across multiple sites, and opened at Princess Margaret Cancer Centre in 7/2016. Clinical trial information: NCT02489006.
A phase II trial of enzalutamide in patients with androgen receptor positive (AR+) ovarian, primary peritoneal or fallopian tube cancer and one, two, or three prior therapies.
Authors: Grisham Rachel N. , Giri Dilip D. , Iasonos Alexia , Zhou Qin , Girshman Jeffrey , McGrath Sean Patrick , O'Cearbhaill Roisin Eilish , Sabbatini Paul , Tew William P. , Hyman David Michael , Hensley Martee Leigh , Zamarin Dmitriy , Konner Jason A. , Snyder Charen Alexandra , Cadoo Karen Anne , Spriggs David R. , Iyer Gopa , Aghajanian Carol
Published: September 2018

TPS5610

Background: Approximately 75% of women with epithelial ovarian cancer (OC) present with advanced disease. Most of these women will ultimately recur and require life-long treatment for their cancer. Well tolerated therapies for treatment in the recurrent setting are needed. The AR is expressed in greater than 60% of cases of OC and is more prevalent than the estrogen or progesterone receptor. All past clinical studies of AR inhibition in OC have focused on unselected populations of heavily pretreated women; however preclinical data suggests that AR expression decreases in OC cells with increasing lines of therapy. Enzalutamide is a small molecule androgen receptor-antagonist that is FDA approved for treatment of prostate cancer and is currently being investigated as treatment for breast and ovarian cancer. Methods: This is a phase II, single-institution trial of enzalutamide 160mg po QD in patients with AR+ ovarian, fallopian tube or primary peritoneal cancer. Eligible patients must be found to have greater than or equal to 5% AR staining by IHC on FFPE tumor tissue and been treated with only 1,2 or 3 prior cytotoxic therapies. Patients must have RECIST 1.1 defined measurable disease. Enrolled patients are treated with enzalutamide until progression of disease or unacceptable toxicity. The primary endpoint is to estimate the proportion of women who achieve a complete or partial response by RECIST 1.1 criteria or survive progression free for at least 6 months. Secondary objectives include the retrieval of optional tumor biopsies at time of progression to evaluate the effect of enzalutamide on AR expression and to observe the effect of enzalutamide on serum testosterone and estradiol levels. This study will enroll 58 patients at Memorial Sloan Kettering Cancer Center and its regional sites. The study utilizes a safety lead-in phase and a two-stage design. The first patient enrolled in April 2015. The safety lead-in phase has been completed. The prespecified activity goal for the first stage was met; second stage accrual began in October 2016. Thus far, 35 patients have initiated treatment. Clinical trial information: NCT01974765.
A randomized controlled trial comparing primary tumor resection plus systemic therapy with systemic therapy alone in metastatic breast cancer (JCOG1017 PRIM-BC).
Authors: Shien Tadahiko , Mizutani Tomonori , Tanaka Kiyo , Kinoshita Takayuki , Hara Fumikata , Fujisawa Tomomi , Masuda Norikazu , Tamura Kenji , Hojo Takashi , Kanbayashi Chizuko , Niikura Naoki , Shibata Taro , Fukuda Haruhiko , Iwata Hiroji
Published: September 2018

TPS588

Background: The possibility of improving the survival of stage IV breast cancer patients by primary tumor resection (PTR) has been reported by several retrospective studies; however, these studies essentially suffer from biases such as arbitrary patient selection, diverse timing of surgery or various regimens of systemic therapy. Five prospective randomized trials including our trial have evaluated the efficacy of PTR for them. Two have reported final results, but those results were inconsistent. Therefore, this subject still remains a hotly debated topic at major breast conferences. Methods: Our trial is being conducted to confirm the superiority of PTR plus systemic therapy over systemic therapy alone in stage IV pts who are sensitive to primary systemic therapy (PST) in this study. The inclusion criteria are untreated pts with histologically confirmed invasive breast cancer with one or more measurable distant metastatic lesions diagnosed by radiological examination.All pts receive PST according to the ER and HER2 status of the primary breast cancer after the first registration. After three months, the pts who are sensitive to PST are randomized to the PTR plus systemic therapy arm or the systemic therapy alone arm. After randomization and surgery in the former arm, or after randomization in the latter arm, the same systemic therapies are continued until progression of diseases and next appropriate regimens are started after that. The primary endpoint is the overall survival, and the secondary endpoints are proportion of pts without tumor progression at the metastatic sites, yearly local recurrence-free survival, proportion of local ulcer/local bleeding, yearly primary tumor resection-free survival, adverse events (AEs) of chemotherapy, operative morbidity, and serious AEs. Sample size for randomized pts was determined to attain at least 80% of power to detect a 6 months difference with one-sided alpha of 0.05.The pts accrual was started in May 2011. Enrollment of 410 pts for randomization is planned over a 7-year accrual period. 307 pts have been randomized until Jan 2017. This trial was registered at UMIN-CTR[umin.ac.jp/ctr/] as UMIN000005586. Clinical trial information: UMIN000005586.
PARTNER: Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients.
Authors: Earl Helena Margaret , Vallier Anne-Laure , Qian Wendi , Grybowicz Louise , Thomas Stanly , Mahmud Saba , Harvey Caron , McAdam Karen , Hughes-Davies Luke , Roylance Rebecca , Copson Ellen , Brown Jessica , Provenzano Elena , McMurtry Emma , Tischkowitz Marc , Abraham Jean
Published: September 2018

TPS591

Background: No specific targeted therapies are available for Triple Negative Breast Cancers (TNBC), an aggressive and diverse subgroup. The basal TNBC sub-group show some phenotypic and molecular similarities with germline BRCA (gBRCA). In gBRCA patients, and potentially other homologous recombination deficiencies, these already compromised pathways may allow drugs called PARP inhibitors (olaparib) to work more effectively. Aims: To establish if the addition of olaparib to neoadjuvant platinum based chemotherapy for basal TNBC and/or gBRCA breast cancer is safe and improves efficacy (pathological complete response (pCR)). Trial design: 3-stage open label randomised phase II/III trial of neoadjuvant paclitaxel and carboplatin +/- olaparib, followed by clinicians' choice of anthracycline regimen. Stage 1 and 2: Patients are randomised (1:1:1) to either control (3 weekly carboplatin AUC5/weekly paclitaxel 80mg/m2 for 4 cycles) or one of two research arms with the same chemotherapy regimen but with two different schedules of olaparib 150mg BD for 12 days. Stage 3: Patients are randomised (1:1) to either control arm or to the research arm selected in stage 2. Methods: Stage 1 - Safety: both research arms combined. Stage 2 - Schedule selection criteria: pCR rate and completion rate of olaparib protocol treatment. It is a “pick-the-winner” design with 53 patients in each research arm. This allows a 90% power, 5% one-sided significance level to test null hypothesis of pCR ≤35% versus an alternative hypothesis of pCR ≥55% in each of the research arms. Stage 3 - Efficacy: anticipated pCR ~55-60% for all trial patients and ~60-65% for gBRCA patients. The trial is powered to detect an absolute improvement of 15% (all patients) and 20% (gBRCA patients) by adding olaparib to chemotherapy (enriched design). TNBC patient recruitment will be capped, to ensure required gBRCA patients are enrolled. Enrichment design is applied with overall significance level 0.05(α) = 0.025(αall)+ 0.025(αgBRCA) and 80% power. Target accrual: 527 [gBRCA 220] Current accrual: 17 Sites activated: 12 [expected number of sites 30-50].
KEYNOTE-412: Pembrolizumab (pembro) in combination with chemoradiation versus chemoradiation alone in locally advanced head and neck squamous cell carcinoma (LA-HNSCC).
Authors: Machiels Jean-Pascal H. , Licitra Lisa , Rischin Danny , Waldron John , Burtness Barbara , Gregoire Vincent , Shekar Tulin , Brown Holly M. , Cheng Jonathan D. , Siu Lillian L.
Published: September 2018

TPS6090

Background: Approximately half of patients (pts) with HNSCC are diagnosed with locally advanced disease and treated with surgery or concomitant chemoradiotherapy (CRT) with cisplatin. Unfortunately, disease recurs in 40% to 60% of patients. The PD-l inhibitor pembro is approved for recurrent/metastatic HNSCC. CRT has immunomodulatory effects; preclinical data suggest that efficacy can be improved by adding pembro. The phase 3 KEYNOTE-412 trial (NCT03040999) will explore if CRT + pembro can improve outcomes of pts with LA-HNSCC. Methods: Adult pts with newly diagnosed, pathologically proven, treatment-naive LA-HNSCC will be enrolled. Study population will include p16-negative HNSCC (any T3-T4 or any N2a-N3 [AJCC 7th edition]) and p16-positive oropharyngeal cancer (any T4 or any N3). Other eligibility criteria: measurable disease per RECIST v1.1 by blinded independent central review (BICR), provision of tumor sample for biomarker analyses, ECOG PS 0 or 1, and eligible for definitive CRT but not considered for primary surgery. Pts will be randomly assigned 1:1 to receive either pembro 200 mg every 3 weeks (Q3W) plus CRT, which includes radiotherapy (RT; accelerated [70 Gy, six 2 Gy fractions/wk] or standard [70 Gy, five 2 Gy fractions/week] fractionation) plus cisplatin 100 mg/m2 Q3W for 3 cycles only, or placebo Q3W plus CRT. Pts will be stratified by RT regimen, tumor site/p16 status, and disease stage. Treatment will continue until centrally confirmed disease progression, unacceptable AEs, decision to withdraw by pt or investigator, or completion of 17 doses of pembro/placebo. Disease status will be evaluated by CT or MRI 12 weeks after end of CRT, every 4 months during the next 2 years, and then every 6 months during years 3-5. Pts will be evaluated for neck dissection at 12 weeks after CRT. AEs will be monitored and graded using CTCAE v4.0 throughout the trial and for 30 days (90 days for serious AEs) after end of treatment. Primary efficacy end point is event-free survival per RECIST v1.1 by BICR. Key secondary end points: overall survival, quality of life, and safety and tolerability of pembro. Approximately 780 pts will be enrolled. Clinical trial information: NCT03040999.
A phase II/III, multicenter, open-label, 3-arm study of gilteritinib, gilteritinib plus azacitidine, or azacitidine alone in the treatment of newly diagnosed FLT3 mutation-positive acute myeloid leukemia (AML) patients ineligible for intensive induction chemotherapy.
Authors: Cortes Jorge E. , Altman Jessica , Ritchie Ellen K. , Larson Richard A. , Claxton David , Minden Mark D. , Goldenberg Alec , Naoe Tomoki , Yoon Sung-Soo , Rousselot Philippe H. , Mueller-Tidow Carsten , del Castillo Teresa Bernal , Havelange Violaine , Ciceri Fabio , Knopinska-Posluszny Wanda , Liu Shufang , Shrivastava Archita , James Angela Joubert , Rich Elizabeth Shima , Bahceci Erkut
Published: September 2018

TPS7068

Background: Gilteritinib, a highly selective, potent FLT3/AXL inhibitor, showed antileukemic activity with favorable tolerability in a Phase 1/2 trial of FLT3 mutation-positive (FLT3mut+) relapsed/refractory AML. In FLT3mut+ AML cell lines, gilteritinib plus azacitidine (AZA) inhibited growth, and induced apoptosis and differentiation. This ongoing Phase 2/3 trial will examine the efficacy, safety, and tolerability of gilteritinib alone, gilteritinib plus AZA or AZA alone in newly diagnosed FLT3mut+AML patients ineligible for intensive induction chemotherapy. Methods: This open-label, 3-arm, 2-stage randomized trial (NCT02752035) will enroll ~540 newly diagnosed adults with FLT3mut+ (FLT3-ITD or -TKD) AML; those with APL, BCR-ABL+, or active CNS leukemia will be excluded. Before initiation, the safety and tolerability of gilteritinib plus AZA will be assessed in a Safety Cohort to establish the appropriate gilteritinib dose for combination therapy. Subjects will then be randomized 1:1:1 to receive oral gilteritinib alone (120 mg daily; Days 1–28), AZA alone (75 mg/m2 by subcutaneous injection or intravenous infusion on Days 1–7), or AZA (75 mg/m2; Days 1–7) plus oral gilteritinib (daily on Days 1–28 at the dose determined from the Safety Cohort), and stratified by age ( < 75 vs ≥75 years). Subjects will continue treatment until a discontinuation event occurs. The primary endpoint is overall survival of subjects receiving gilteritinib or gilteritinib plus AZA versus AZA alone; the key secondary endpoint is event-free survival. Additional secondary endpoints: complete remission rate, leukemia-free survival, remission duration, composite remission rate, tolerability, and fatigue. Dose changes and interruptions are allowed in all treatment arms. A formal interim futility analysis by an Independent Data Monitoring Committee is planned when ~50 subjects in each treatment arm have either discontinued therapy or completed 2 treatment cycles. Enrollment began on November 21, 2016; as of January 31, 2017, the Safety Cohort is ongoing. Clinical trial information: NCT02752035.
H3B-8800-G0001-101: A first in human phase I study of a splicing modulator in patients with advanced myeloid malignancies.
Authors: Steensma David P. , Maris Michael B. , Yang Jay , Donnellan William Bruce , Brunner Andrew M , McMasters Malgorzata , Greenberg Peter , Komrokji Rami S. , Klimek Virginia M. , Goldberg John M. , Rioux Nathalie , Kim Amy , Kumar Pavan , Marino Alyssa J. , Buonamici Silvia , Smith Peter , Sahmoud Tarek , Warmuth Markus , Platzbecker Uwe
Published: September 2018

TPS7075

Background: Dysregulated mRNA splicing is important in tumorigenesis and in resistance to cancer therapy. Somatic heterozygous mutations in core spliceosome genes (e.g. SF3B1, SRSF2, U2AF1) have been reported at high frequencies in patients with myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and chronic myelomonocytic leukemia (CMML). These mutations confer a change of function resulting in aberrant mRNA splicing that, in preclinical models, results in defects in hematopoietic cell development and myelodysplasia. Recurrent mutations in the spliceosome of patients with malignancies suggests importance in disease pathogenesis. Cells bearing splicing mutations depend on wild-type spliceosome function, suggesting the spliceosome as a therapeutic target. In vitro data indicate preferential induction of apoptosis (measured by caspase 3/7 activation) in SF3B1-mutant cells following treatment with the SF3B1 modulator H3B-8800. H3B-8800 inhibits growth in human AML cell lines, including those with mutations in U2AF1, SRSF2 or SF3B1. Oral administration of H3B-8800 modulates splicing and induces antitumor activity in xenograft leukemia models expressing mutant core spliceosome components. Methods: This study explores the safety of H3B-8800 in patients with myeloid cancers. Dose escalation (Cohort A) follows a 3+3 design with a starting dose of 1 mg daily for 5 consecutive days every 14 days in a 28 day cycle. Cohort A is open to patients with MDS, AML or CMML, irrespective of spliceosome mutations. In parallel to dose escalation, up to 6 patients with mutations of interest may be enrolled at doses determined to be safe in Cohort A (Cohort B). After determining the recommended phase 2 dose, 4 expansion cohorts will enroll patients with: (1) International Prognostic Scoring System (IPSS) low/int-1 risk MDS with SF3B1 mutations, (2) IPSS low/intermediate risk-1 MDS with mutations in SRSF2, U2AF1, or ZRSR2, (3) high/intermediate risk-2 MDS or AML, and (4) CMML; 3 and 4 having mutations in SF3B1, SRSF2, U2AF1, or ZRSR2. The first cohort enrolled 3 patients and the trial is currently enrolling patients at the second dose level. Clinical trial information: NCT02841540.
Zuma-6: Phase 1-2 multicenter study evaluating safety and efficacy of axicabtagene ciloleucel (axi-cel; KTE-C19) in combination with atezolizumab in patients with refractory diffuse large b-cell lymphoma (DLBCL).
Authors: Locke Frederick Lundry , Westin Jason R. , Miklos David Bernard , Herrera Alex Francisco , Jacobson Caron Alyce , Lee Lillian , Rossi John , Bot Adrian , Xue Allen , Navale Lynn , Aycock Jeff , Wiezorek Jeffrey S. , Roberts Zachary
Published: September 2018

TPS7572

Background: Approximately 1/3 of patients with DLBCL, the most common type of B-cell lymphoma, will become refractory to standard combination chemotherapy and have uniformly poor clinical outcomes (Crump, ASCO 2016). Axi-cel (autologous anti-CD19 chimeric antigen receptor [CAR] T cell therapy) has shown promising response rates in patients with refractory DLBCL compared with standard approaches, although some patients do not respond or progress after an initial response (Locke, Mol Ther 2016). Expression of PD-L1 on DLBCL cells and activation-dependent expression of PD-1 on CAR T cells after infusion led to the hypothesis that PD-1 pathway blockade may augment the activity of axi-cel and result in improved clinical outcomes. This study will evaluate safety and efficacy of axi-cel when given with atezolizumab (anti–PD-L1 antibody), delivered sequentially, in patients with refractory DLBCL. Methods: Phase 1 will enroll ~3-9 patients to estimate the incidence of dose-limiting toxicities. Phase 2 will enroll ~22 patients to evaluate safety and efficacy, with a primary endpoint of complete response (CR) rate (Cheson 2007). Secondary endpoints include key efficacy outcomes such as objective response rate (CR+partial response [PR]), duration of response, progression-free and overall survival, and safety and biomarker outcomes. Eligible adult patients will have received prior adequate therapy (including anti-CD20 monoclonal antibody and an anthracycline-based regimen) and have an ECOG PS of 0-1 and adequate bone marrow and organ function. Patients with a history of Richter transformation, transformed follicular lymphoma, CNS disease, or active infection are not eligible. Patients will receive fludarabine 30 mg/m2/d and cyclophosphamide 500 mg/m2/d × 3 d, followed by a single infusion of axi-cel (target dose, 2 × 106anti-CD19 CAR T cells/kg) followed by atezolizumab 1200 mg given every 21 d for 4 doses (phase 1, first dose to occur 21, 14, and 1 d after axi-cel infusion in cohorts 1, 2, and 3, respectively). The study opened to accrual in September 2016. Clinical trial information: NCT02926833.
Phase I/II study of durvalumab (anti–PD-L1 antibody) as monotherapy and in combination in patients with lymphoma or chronic lymphocytic leukemia.
Authors: Witzig Thomas E. , Casulo Carla , Cartron Guillaume , Ruan Jia , Rule Simon , Ando Kiyoshi , Burton Cathy , Pinto Antonio , Le Gouill Steven , Fowler Nathan Hale , Zinzani Pier Luigi , De Bedout Sabine , Kilavuz Nurgul , Rettby Nils , Czuczman Myron Stefan , Santoro Armando ,   And the MEDI4736-NHL-001 Trial Investigators
Published: September 2018

TPS7574

Background: The PD-1/PD-L1 pathway is an important immune checkpoint used by tumor cells to evade immune cell detection and inhibit antitumor responses. PD-1/PD-L1 expression in multiple hematologic malignancies may provide an effective target for enhancing anticancer immune response. Durvalumab (MEDI4736) is a high-affinity human IgG1 monoclonal Ab that selectively blocks PD-L1 binding to PD-1 and CD80, and has shown preliminary evidence of antitumor activity across multiple tumor types. Study objectives are to evaluate durvalumab monotherapy and combinations to determine dose and safety, as well as identify histologies and combinations that show the best complementary antitumor signals for future study. Methods: This is a phase I/II open-label, global, multicenter study of durvalumab as a monotherapy and in combination in relapsed/refractory B-cell lymphoma or CLL (MEDI4736-NHL-001; EUDRA CT 2015-003516-21; NCT02733042). Patients must have histologically-confirmed FL, MCL, splenic or nodal MZL, T-cell/histiocyte rich BCL, PMBCL, ALK+ large BCL, transformed large BCL, Richter’s transformation, DLBCL (NOS), CLL/SLL, or classical HL during the dose-finding part. Inclusion criteria are ECOG PS 0-2, and ≥1 prior antilymphoma therapy. Up to 253 patients may enroll in 4 treatment arms, which include fixed-dose durvalumab 1500 mg Q4W monotherapy or combinations with lenalidomide/rituximab, ibrutinib, or bendamustine/rituximab. The study has 3 parts: dose finding, dose confirmation, and dose expansion. The monotherapy arm does not have a dose finding or expansion part; upon progression, patients may receive combination therapy or involved-field radiation to a single nodal site (evaluating for systemic abscopal antitumor effect). Primary endpoints are safety, identification of recommended phase II dose (phase I, 3+3 design), and overall response rate (ORR; phase II); secondary endpoints include DOR, PFS, and PK/PD. ORR is measured by 2014 IWG criteria for lymphoma or modified 2008 iwCLL criteria for CLL; safety is assessed per NCI CTCAE v4.03 criteria. Recruitment is ongoing, with a target enrollment of 253 patients across 60-80 centers globally. Clinical trial information: NCT02733042.
Phase 1 study to evaluate the safety and efficacy of immunotherapy with tremelimumab and durvalumab in multiple myeloma patients receiving high dose chemotherapy and autologous stem cell transplant (HDT/ASCT) + peripheral blood lymphocyte (PBL) reinfusion.
Authors: Lesokhin Alexander M. , Chung David J. , Cho Hearn J. , Shohara Lisa , Schwarzenberger Paul , Ricciardi Toni , Macri Mary J. , Ryan Aileen , Venhaus Ralph Rudolph
Published: September 2018

TPS8051

Background: Multiple myeloma (MM) remains an incurable hematologic malignancy despite the advent of new classes of drugs, including immunomodulatory agents, proteasome inhibitors, and monoclonal antibodies. The success and synergistic activity of immunotherapy (IMT) in solid tumors and hematologic malignancies has fueled their investigation in MM. HDT/ASCT as consolidation or as treatment for relapse remains a cornerstone for improving overall survival. HDT/ASCT transiently eliminates immune-suppressive cell populations and provides a viable IMT platform. Reinfusion of PBLs harvested pre-HDT induces immune responses, supporting its inclusion in IMT combinations. This study evaluates the effect of IMT, using tremelimumab (T), an anti-CTLA-4 monoclonal antibody, and durvalumab (D), an anti-PD-L1 monoclonal antibody, together with autologous PBL reinfusion and starting T ± D at Day 100 and earlier (Day 30) post-ASCT. Methods: This ongoing Phase 1, open-label, multicenter study (NCT02716805) evaluates the safety and preliminary efficacy of T and D administered on 2 schedules in MM patients at high risk for relapse as outlined below. Cohort initiation requires dose-limiting toxicity in < 2/6 patients in the previous cohort. The primary endpoint is safety. Secondary endpoints are objective response rate per IMWG, minimal residual disease, progression free and overall survival, and 100-day ASCT-related mortality. Exploratory endpoints include immunological effects and immune response. Enrollment opened 18 Nov 2016. As of 31 Dec 2016, 1 patient is enrolled in Cohort 1; enrollment is ongoing. Clinical trial information: NCT02716805. [Table: see text]
A phase 1/2 study of durvalumab (DURVA) in combination with lenalidomide (LEN) with or without dexamethasone (DEX) in patients (pts) with newly diagnosed multiple myeloma (NDMM).
Authors: Lonial Sagar , Oriol Albert , Mateos Maria-Victoria , Rodriguez-Otero Paula , Bahlis Nizar J. , Bensinger William , Porkka Kimmo , Van De Donk Niels , Yiu Wai , Di Casoli Carl , Ervin-Haynes Annette L. , Zaki Mohamed H. , Vangsted Annette
Published: September 2018

TPS8055

Background: LEN + DEX (Rd) is approved for pts with newly diagnosed MM, including those who are transplant non-eligible (TNE). DURVA is a monoclonal antibody to programmed death ligand 1 (PD-L1) that blocks PD-L1 binding to programmed death-1 (PD-1). Preclinical studies showed anti-MM immune responses with PD-1/PD-L1 blockade that were enhanced with LEN (Görgün et al, 2015). Here, we present a phase 1/2, multicenter, open-label trial in progress (MEDI4736-MM-002) designed to evaluate DURVA in combination with LEN ± DEX in a target population of pts who are TNE and/or with high-risk NDMM. Methods: Enrollment of up to 138 pts from the US, Canada, and Europe is planned to determine the recommended dose of DURVA (primary endpoint) with LEN ± DEX for the treatment (Tx) of NDMM. Key secondary endpoints include safety, response outcomes, pharmacokinetics, progression-free survival, and overall survival. Pts with previously untreated MM with ≥ 1 of the following will be included: 1 of the CRAB criteria or clonal bone marrow plasma cells ≥ 60% and an Eastern Cooperative Oncology Group performance status of ≤ 2. Pts with a history of primary immunodeficiency will be excluded. Each independent cohort (A, B, C) will enroll 6 pts in parallel in the dose-finding phase (Table). Dose-limiting toxicities will be evaluated during the first cycle of Tx. The optimal regimen will be determined from the dose-finding phase and a parallel dose-expansion phase of up to 40 pts per cohort. Tx will continue until progressive disease or unacceptable toxicity. To date, 15 pts have enrolled. Clinical trial information: NCT02685826. [Table: see text]
Phase 2, open-label study of venetoclax in combination with carfilzomib and dexamethasone in patients with relapsed/refractory multiple myeloma.
Authors: Bueno Orlando , Xu Tu , Cordero Jaclyn , Morris Lura , Ross Jeremy , Freise Kevin , Munasinghe Wijith , Leverson Joel , Mudd Sarah , Verdugo Maria
Published: September 2018

TPS8056

Background: A significant unmet need for multiple myeloma (MM) therapy remains as many patients eventually relapse after or become refractory to current treatment options. Investigation of novel agents and combinations in relapsed/refractory (R/R) patients are therefore critical to advance therapy and improve patient outcomes. Venetoclax is a potent, selective, orally bioavailable inhibitor of BCL-2. Combination of venetoclax with dexamethasone and bortezomib, a proteasome inhibitor that can inhibit MCL-1 indirectly via stabilizing the MCL-1-neutralizing protein NOXA, showed high rates of clinical response in a Phase 1 study. The mechanism of MCL-1 inhibition is thought to be a class effect of proteasome inhibitors. Given the clinical data supporting the combination of venetoclax with a proteasome inhibitor, this study will evaluate whether venetoclax combined with carfilzomib and dexamethasone can provide a well-tolerated and efficacious treatment option for R/R MM patients. Methods: This Phase 2, open-label study will assess the combination of venetoclax, carfilzomib, and dexamethasone in patients with R/R MM (NCT02899052). Primary objectives are to assess the safety and tolerability of this combination. Secondary objectives include evaluation of the pharmacokinetics of venetoclax and carfilzomib, preliminary efficacy of the combination (including overall response rate, very good partial response or better rate, progression-free survival, time to progression, and duration of response), and minimal residual disease (MRD) in bone marrow by next generation sequencing. Exploratory objectives will assess pharmacodynamic and predictive biomarkers, MRD by PET, pharmacogenetics, and patient-reported outcomes. Safety and pharmacokinetic profiles of the combination will be evaluated in initial dose escalation cohorts to determine appropriate doses of venetoclax and carfilzomib to be used with dexamethasone; a dose expansion phase will evaluate the safety and efficacy profiles of the combination based on selected doses. Study recruitment began in January 2017, with target enrollment of ~40 patients from 10–15 sites in the United States. Clinical trial information: NCT02899052.
A phase II study of atezolizumab as neoadjuvant and adjuvant therapy in patients (pts) with resectable non-small cell lung cancer (NSCLC).
Authors: Owen Dwight Hall , Bunn Paul A. , Johnson Bruce E. , Kwiatkowski David J. , Kris Mark G. , Wistuba Ignacio Ivan , Gandhi Mayank , Phan See , Shames David S. , Schulze Katja , Yu Wei , Aisner Dara , Chaft Jamie E. , Garon Edward B. , Lee Jay M , Minna John D. , Rusch Valerie W. , Reckamp Karen L. , Wozniak Antoinette J. , Carbone David P. ,   LCMC3 Investigators
Published: September 2018

TPS8580

Background: Trials of neoadjuvant and adjuvant chemotherapy have demonstrated an absolute survival benefit of 5% for patients with early stage disease. Atezolizumab is a humanized IgG1 monoclonal antibody that inhibits PD-L1 from binding to its receptors PD-1 and B7.1, thereby restoring anti-tumor immune response. In the OAK trial, a randomized phase III trial of patients with metastatic NSCLC who progressed on platinum based chemotherapy, atezolizumab improved overall survival in patients regardless of PD-L1 expression compared with docetaxel (13.8 months vs. 9.6 months, HR 0.73 [95% CI 0.62 – 0.87]) with a manageable safety profile. Methods: NCT02927301 is a phase II, open-label, single-arm study designed to evaluate the efficacy and safety of atezolizumab as a neoadjuvant and adjuvant therapy in patients with Stage IB, II, or IIIA NSCLC prior to curative-intent resection. Approximately 180 patients with NSCLC will be enrolled in this study at 15 academic medical centers in the United States. The study has two parts: the primary part will evaluate the ability of neoadjuvant atezolizumab to produce pathologic responses in patients with early stage NSCLC. Atezolizumab 1200 mg IV will be given every 3 weeks for two doses. Surgical resection of tumors following treatment will allow determination of pathologic response rates and potential predictive biomarkers. Part 2 is exploratory and will evaluate atezolizumab adjuvant therapy for up to 12 months in patients who demonstrate clinical benefit in Part 1. The primary endpoint is major pathologic response rate (defined as ≤ 10% of viable tumor tissue) based on surgical resection. Secondary end points include overall response rate by status of mutation load, neoantigen score and gene expression signatures. OS and DFS are exploratory end points. This trial presents a unique opportunity to evaluate exploratory biomarkers given the availability of pre- and post-treatment biopsy specimens for assessment of evolution of immune related markers associated with response. The study opened to accrual in January 2017. Clinical trial information: NCT02927301.
Phase I/III trial of atezolizumab with carboplatin and etoposide in ES-SCLC in first-line setting (IMpower133).
Authors: Horn Leora , Mansfield Aaron Scott , Reck Martin , Mok Tony , Spira Alexander I. , Tang Xiongwen , Lam Sivuonthanh , Kabbinavar Fairooz F. , Lopez-Chavez Ariel , Sandler Alan , Liu Stephen V.
Published: September 2018

TPS8584

Background: The first-line standard of care for the majority of patients (pts) with extensive-stage small-cell lung cancer (ES-SCLC) is platinum-based chemotherapy with etoposide, but survival outcomes remain poor (median OS, < 1 year) despite initial response rates ranging from 50-70%. Atezolizumab (atezo), an anti–PD-L1 mAb, prevents the binding of PD-L1 with its receptors PD-1 and B7.1 and restores anticancer T-cell activity. Tolerable safety with promising durability of response has been shown with atezo in pts with ES-SCLC: confirmed ORR was 6% (n = 1/17 [partial response]; DOR of 7 mo) by RECIST v1.1 and 24% by immune-related response criteria (irRC; n = 4/17, with 2 pts on atezo for ≥ 12 mo). Preliminary data also indicate the potential synergy between atezo and platinum-based chemotherapy in NSCLC, whereby durable responses may translate into improved survival over atezo alone. IMpower133 (NCT02763579), a global, Phase I/III, randomized, multicenter, double-blinded, placebo-controlled trial will evaluate the efficacy and safety of 1L atezo + carboplatin + etoposide compared with placebo + carboplatin + etoposide in treatment-naive pts with ES-SCLC. Methods: Pts with measurable (RECIST v1.1) ES-SCLC, who have ECOG PS 0-1 and no prior systemic anticancer treatment, are eligible for the study. Exclusion criteria include untreated CNS metastases and history of autoimmune disease. The study requires submission of tumor tissue, but pts will be enrolled regardless of biomarker status. Pts will be stratified by sex, ECOG PS and presence of treated brain metastases. Eligible pts will be randomized 1:1 to receive four 21-day cycles of atezo (1200 mg IV) or placebo in combination with carboplatin (AUC 5 mg/mL/min IV, d 1) and etoposide (100 mg/m2 IV, d 1-3), followed by maintenance therapy with atezo or placebo until PD per RECIST v1.1. Pts can continue with treatment until persistent radiographic PD, symptomatic deterioration or unacceptable toxicity. Co-primary endpoints are investigator-assessed PFS per RECIST v1.1 and OS. Secondary efficacy endpoints include investigator-assessed ORR and DOR. Safety and tolerability will also be assessed. Approximately 400 pts will be enrolled. Clinical trial information: NCT02763579.
NIVORAD: A randomised phase 2 trial of nivolumab and stereotactic ablative body radiotherapy in advanced non-small cell lung cancer, progressing after first or second line chemotherapy.
Authors: Mitchell Paul , Siva Shankar , Kok Peey Sei , O'Byrne Ken , Yeung Annie , Livingstone Ann , Donoghoe Mark , Yip Sonia , Stockler Martin R. ,   Australasian Lung Cancer Trials Group (ALTG)
Published: September 2018

TPS9097

Background: Recent data has demonstrated improvements in overall survival in patients with advanced non-small cell lung cancer (NSCLC) treated with nivolumab. Radiation may augment the immune response through abscopal effects - evidence of tumour control at sites other than those irradiated. We hypothesize that the addition of stereotactic ablative body radiotherapy (SABR) to immunotherapy with nivolumab will improve progression free survival (PFS) compared with nivolumab alone. Methods: DESIGN: Open label, randomised phase II trial with 25 sites across Australia and New Zealand. ELIGIBILITY: Metastatic NSCLC progressing after 1 or 2 lines of chemotherapy with an extrapulmonary metastasis suitable for SABR. STRATIFICATION: Age, lines of chemotherapy, histology and treating institution. TREATMENT: A single dose of SABR (18-20Gy) plus nivolumab or nivolumab alone (240mg 2-weekly) given until disease progression or prohibitive adverse events. ENDPOINTS: PFS at 6 months (PFS6; primary), objective tumour response rate, adverse events, overall survival, PFS at 1 and 2 years. Tertiary correlative objectives include associations between possible prognostic/ predictive biomarkers and outcomes (including PD-L1 expression). STATISTICS:Total sample size of 120 participants allocated in a ratio of 2:1, 80 to nivolumab + SABR and 40 nivolumab alone to provide 80% power, one-sided type I error rate of 5% for PFS6 of 50% (worthy of pursuit) vs 35% (not worthy of pursuit). BIOSPECIMENS: Tumour tissue and serial bloods (4 time points) will be collected for translational research. CURRENT ENROLLMENT (as of Feb 2017): 2 out of 20 sites are open. NIVORAD is an investigator-initiated, cooperative-group trial led by the ALTG in collaboration with the NHMRC Clinical Trials Centre, University of Sydney and the Trans Tasman Radiation Oncology Group (TROG). Australian New Zealand Clinical Trials Registry: ACTRN12616000352404.