On June 1, 2019 Replimune Group, Inc. (NASDAQ: REPL), a biotechnology company developing oncolytic immuno-gene therapies derived from its Immulytic platform, reported that the Phase 2 portion of the Company’s Phase 1/2 clinical trial of RP1 alone and in combination with nivolumab anti-PD1 therapy has initiated (Press release, Replimune, JUN 1, 2019, View Source [SID1234536762]). In the Phase 2 portion of the clinical trial, RP1 in combination with nivolumab will be tested in four 30-patient cohorts of patients with melanoma, non-melanoma skin cancers (NMSC), metastatic bladder cancer or microsatellite instability-high (MSI-H) tumors. Enrollment is now open in the melanoma, NMSC and bladder cancer cohorts, and enrollment in the MSI-H cohort will open as soon as a protocol-required MSI-H patient is evaluable from Phase 1. The patients enrolled into the melanoma cohort either will be treatment naïve or have received one prior systemic therapy, and the patients enrolled into the other three cohorts will all be naïve to anti-PD1 therapy.

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Data relating to the Phase 1 portion of the clinical trial, including biomarker data, is expected to be presented at a medical conference in the fourth quarter of 2019. The Phase 1 portion tested single agent RP1 by direct injection into a single superficial or nodal tumor and by imaging guided injection into a single visceral tumor in patients with advanced heavily pre-treated cancers who failed available therapy to define the recommended Phase 2 dose. Following determination of the recommended Phase 2 dose, an expansion group of advanced cancer patients who failed available therapy then received RP1 at the recommended Phase 2 dose in combination with nivolumab at standard clinical doses.

Poster Presentation at ASCO (Free ASCO Whitepaper)
The Company also announced that a trial in progress (TiP) poster will be presented today at the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting currently being held in Chicago, IL. The poster describes the design and current status of the Phase 1/2 clinical trial, including the tumor types of the patients enrolled, and will be made available on the Company’s website at the time of presentation.

Details of Replimune’s poster presentation:

Abstract Title: An Open-Label, Multicenter, Phase 1/2 Study of RP1 as a Single Agent and in Combination with PD1 Blockade in Patients with Solid Tumors (Abstract TPS2671)

Session Title: Developmental Immunotherapy and Tumor Immunobiology

Session Date and Time: Saturday June 1st, 8:00am-11:00am CDT

Location: McCormick Place, Exhibit Hall A, Poster Board #301b

About RP1
RP1 is Replimune’s first Immulytic product candidate to enter the clinic and is based on a proprietary new strain of herpes simplex virus engineered to maximize tumor killing potency, the immunogenicity of tumor cell death and the activation of a systemic anti-tumor immune response.

On June 1, 2019 Mersana Therapeutics, Inc. (Nasdaq: MRSN), a clinical-stage biopharmaceutical company focused on discovering and developing a pipeline of antibody drug conjugates (ADCs) targeting cancers in areas of high unmet medical need, reported new interim efficacy and safety data from its ongoing Phase 1 dose-escalation study evaluating XMT-1536, its first-in-class ADC candidate targeting NaPi2b, in patients with ovarian cancer, non-small cell lung (NSCLC) adenocarcinoma and other tumor types (Press release, Mersana Therapeutics, JUN 1, 2019, View Source [SID1234536916]). The data will be presented in a poster session and poster discussion today at the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting being held from May 31 — June 4, 2019 in Chicago, IL.

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"We are encouraged by the early signs of efficacy coupled with the favorable safety and tolerability profile and promising treatment duration we have seen to date in this ongoing Phase 1 study with XMT-1536 in heavily pre-treated, advanced cancer patients," said Anna Protopapas, President and CEO, Mersana Therapeutics. "We look forward to moving into the dose expansion phase of the study which will focus on platinum-resistant ovarian cancer and NSCLC adenocarcinoma patient populations."

In a poster titled "Phase 1 dose escalation study of XMT-1536, a novel NaPi2b-targeting antibody-drug conjugate (ADC), in patients (pts) with solid tumors likely to express NaPi2b," Mersana demonstrated that as of May 10, 2019, XMT-1536 is well tolerated at doses up to 30 mg/m2, with observation of objective responses at 20 mg/m2 and higher. Of the 37 patients enrolled, tumor types included 22 ovarian, fallopian tube or primary peritoneal cancer, four NSCLC, eight endometrial, two papillary renal, and one salivary duct cancer. Patients were heavily pre-treated, with a median of four prior lines of treatment (range 1-13) for all patients and a median of five lines of prior treatment in ovarian cancer patients (range 1-11). Interim results included:

· The most common treatment-related adverse events (TRAEs) were Grade 1-2 nausea, fatigue, and headache, and the most frequent Grade 3 TRAE was transient AST elevation.

· In patients with tumor types selected for the planned expansion phase (platinum-resistant ovarian cancer and NSCLC adenocarcinoma) treated at >20 mg/m2 (N=18), three (17%) achieved partial responses (PRs) and eight (44%) achieved stable disease (SD) for a disease control rate (DCR) of 11/18 (61%), and a treatment duration lasting beyond 16 weeks in 9 patients (50%).

· In ovarian cancer patients treated at >30 mg/m2 (N=7), two (28%) achieved partial responses (PRs) and three (43%) achieved stable disease (SDs) for a disease control rate (DCR) of 5/7 (71%), and three of these patients (43%) were treated on study for more than 16 weeks.

The Company continues to evaluate patients in the dose escalation portion of the study in the once-every-four-week dose level of 36 mg/m2. Upon completion of the 36 mg/m2 evaluation, the Company expects to choose either the 30 mg/m2 or 36 mg/m2 every four weeks as the go forward dose for the dose expansion phase of the study. Mersana is planning to begin dosing patients in the dose expansion phase in third quarter of 2019.

On June 1, 2019 Sierra Oncology, Inc. (SRRA), a late-stage drug development company focused on advancing targeted therapeutics for the treatment of patients with significant unmet needs in hematology and oncology, reported positive preliminary clinical data from its two first-in-human Phase 1/2 studies of SRA737, a highly selective oral Chk1 inhibitor, as monotherapy and as SRA737+LDG (SRA737 potentiated by low dose gemcitabine), at the 2019 Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago (Press release, Sierra Oncology, JUN 1, 2019, View Source [SID1234536764]). Anti-cancer activity was demonstrated across multiple indications and genetic contexts, with SRA737+LDG specifically achieving a notable 30% response rate in anogenital cancer patients.

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"In collaboration with Dr. Udai Banerji, Chief Investigator, The Institute of Cancer Research (ICR) and The Royal Marsden NHS Foundation Trust, we have established proof-of-concept clinical data for SRA737 and identified a potential clinical indication that could be pursued towards registration," said Dr. Nick Glover, President and CEO of Sierra Oncology. "Our strategy has been to execute a cutting-edge signal-seeking survey of a broad cancer landscape, across both a range of indications and a spectrum of genetic contexts associated with replication stress (RS). The resulting clinical data demonstrate that SRA737 has demonstrable anti-cancer activity in multiple indications, in particular in combination with LDG, and has a favorable tolerability profile, opening up several attractive development paths forward for this unique drug candidate. Of note, we have recently received management support from a major immuno-oncology company to potentially supply their leading immunotherapeutic agent to run a combination study with SRA737. We will further analyze these opportunities and evaluate next steps with this asset over the coming months, exploring options to enable the continued advancement of SRA737 in the context of our emerging pipeline."

"These clinical data provide clear evidence of anti-tumor activity with SRA737+LDG and demonstrate that the combination is well tolerated. Of particular note were the promising responses we observed in squamous cell anogenital/cervical cancers in previously treated patients with advanced disease," said Dr. Rebecca Kristeleit, Clinical Senior Lecturer and Honorary Consultant Medical Oncologist at University College London (UCL) Cancer Institute & UCLH Dept. of Oncology. "In my opinion, SRA737+LDG warrants additional registration-intent clinical development focused on patients with anogenital cancer, an indication for which the second line metastatic setting represents a significant unmet medical need with no approved therapies and very poor life expectancy."

"We are pleased that these signal-generating studies provided compelling support for our original hypothesis that SRA737’s anti-cancer activity was correlated with specific genetic contexts. Indeed, our clinical data demonstrate that anogenital cancer represents a synthesis of overlapping replication stress genetics, providing particular sensitivity to SRA737+LDG. Moreover, these findings support that low dose gemcitabine acts as an exogenous driver of RS that further potentiates SRA737’s anti-cancer activity," said Dr. Christian Hassig, Chief Scientific Officer, Sierra Oncology. "From a safety perspective, our data support that SRA737 and SRA737+LDG are conducive to development in combination with other therapeutic approaches, providing paths for further development with PARP inhibitors and with immunotherapy, combinations for which we have previously reported robust synergistic preclinical efficacy."

The company will be hosting an Analyst and Investor Event on Monday June 3, 2019, to discuss these clinical findings and potential next steps in the development strategy for SRA737+LDG. The event will feature presentations by distinguished oncologists Professor Johann de Bono and Dr. Rebecca Kristeleit.

SRA737+LDG (SRA737-02) First-in-Human Phase 1/2 Preliminary Results
This signal-seeking Phase 1/2 study (NCT02797977) was designed to investigate the safety and tolerability of SRA737 in combination with sub-therapeutic, low dose gemcitabine (LDG), as well as to evaluate preliminary anti-tumor activity of SRA737 potentiated by LDG in tumors with genetic alterations predicted to confer increased intrinsic RS and Chk1i sensitivity. Relative to standard-of-care, gemcitabine doses tested were approximately 10-25% of a standard chemotherapeutic dose.

Preliminary Efficacy Results (Evaluable Patients):

Striking anti-tumor activity was observed in subjects with advanced anogenital cancer (Overall Response Rate (ORR) = 30%; Disease Control Rate (DCR) = 60%), encompassing noteworthy tumor decreases (e.g. -66% tumor decrease; resolution of pleural effusion) and promising durations of treatment (e.g. ~11 months).
Overall, Partial Responses were observed in six subjects and 41 subjects had a best response of Stable Disease (SD); durable SD lasting ≥ 4 months was recorded in 32 subjects and was observed in all expansion cohorts.
The combination of SRA737+LDG was generally well tolerated. There was no evidence of emergent or cumulative toxicity and/or declining tolerability with up to 13 cycles of treatment. At the time of the data cut off (May 3, 2019), 22 subjects remained on study treatment.
Based on overall tolerability, the recommended Phase 2 dose is 500 mg SRA737 + 250 mg/m2 LDG.
Genetic Analyses:

Preliminary evidence suggests several intrinsic sources of RS combined with LDG significantly enhance Chk1 activity.
FA/BRCA gene network mutations were associated with the most favorable outcomes in this study (ORR = 25%; DCR = 81%). The FA/BRCA gene network encodes a series of Fanconi Anemia and other proteins involved directly or indirectly in replication fork metabolism and management of RS.
Mutations in the PI3K gene network correlated with robust DCR (75%) and tumor responses in two subjects, consistent with previous reports of Chk1i sensitivity associated with PIK3CA mutations.
A preliminary correlation of noteworthy tumor responses with elevated tumor mutational burden (TMB) was also observed, particularly in the anogenital cohort (three of four TMB patients achieved notable tumor decreases). Elevated TMB is consistent with increased genomic instability and represents a possible future enrichment strategy.
SRA737-01 Monotherapy First-in-Human Phase 1/2 Preliminary Results
This signal-seeking Phase 1/2 study (NCT02797964) was designed to investigate the safety and tolerability of continuous, oral daily dosing of SRA737, as well as to survey a broad range of cancer indications and genetic contexts in the expansion phase, in order to evaluate preliminary anti-tumor activity and delineate potential genetic signatures and/or tumor indications that might warrant additional therapeutic investigation.

Preliminary Efficacy Results (Evaluable Patients):

The maximum tolerated dose was 1000 mg per day, and based on overall tolerability and PK, the recommended monotherapy dose is 800 mg per day, highlighting the tolerability of SRA737.
Evidence of anti-tumor activity was observed in subjects with HGSOC, colorectal, prostate and non-small cell lung cancer; no RECIST PRs or CRs were confirmed, but several noteworthy tumor reductions were recorded.
HGSOC appeared as the most sensitive tumor to SRA737 monotherapy in the SRA737-01 study. Although heavily pre-treated (~5 prior lines), the HGSOC cohort demonstrated directionally favorable disease control (DCR = 54%) with notable maximal tumor reductions of 29% and 27% in two patients.
A best overall response of stable disease (SD) was seen in 34 (32%) subjects. At the time of the data cut off, durable SD lasting ≥ 4 months was recorded in 22 (21%) subjects and was observed in all Cohort Expansion phase tumor types except head and neck cancer.
Genetic Analyses:

Subjects whose tumors harbored FA/BRCA network mutations, regardless of indication, displayed favorable outcomes (DCR = 71%; DOS = 3.8 cycles), consistent with similar observations in subjects treated with SRA737+LDG.
Within the FA/BRCA pathway, several notable tumor decreases occurred in subjects harboring two genetic alterations, such as a DDR checkpoint kinase gene or within the PI3K network. This phenomenon was also observed in the SRA737+LDG clinical study.
Alterations in the PI3K gene network (PIK3CA, AKT, PTEN) were associated with a 77% DCR.
No clear trend toward enhanced sensitivity was noted with CCNE1 gene amplification, although the small subset of subjects enrolled with unambiguous CCNE1 amplifications renders definitive conclusions challenging.
The majority of subjects with notable responses (tumor reduction and/or >4 months SD) harbored alterations in either or both the PI3K and FA/BRCA gene networks. CCNE gene network alterations (DCR = 67%) partially overlapped with FA/BRCA subjects but was mutually exclusive with PI3K network alterations.
Overall, these data provide promising evidence of SRA737 anti-tumor activity and identify several gene networks associated with potentially enhanced SRA737 sensitivity.
SRA737 Analyst & Investor Event
The company will be hosting an Analyst and Investor Event on Monday, June 3, 2019, to discuss these clinical findings and potential next steps in the development strategy for SRA737+LDG.

Date and Time: June 3, 2019, 6:00 – 7:00 am CT
Location: History event room, Marriot Marquis Hotel, 2121 S Prairie Ave, Chicago, Illinois.

The event will feature presentations by two distinguished oncologists:

Professor Johann de Bono, Regius Professor of Cancer Research, Head of the Division of Clinical Studies and Professor in Experimental Cancer Medicine at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, will discuss the critical role of Chk1 in tumor cell survival during replication stress, as well as describe potential opportunities to combine SRA737 with other therapeutic modalities including PARP inhibitors and immunotherapy agents.
Dr Rebecca Kristeleit, Clinical Senior Lecturer and Honorary Consultant Medical Oncologist at University College London (UCL) Cancer Institute & UCLH Dept. of Oncology, a leading expert in gynecological malignancies, will discuss her clinical experience with SRA737+LDG, and potential development opportunities for this novel combination in the treatment of anogenital cancers.
Event registration and webcast information are available through the Sierra Oncology website at www.sierraoncology.com. An archive of the presentation will be accessible after the event through the Sierra Oncology website.

ASCO 2019 Poster Presentations
Title: A Phase 1/2 First-in-Human Trial of Oral SRA737 (a Chk1 Inhibitor) in Subjects with Advanced Cancer.
Abstract: 3094; Poster #: 86
Poster Session: Developmental Therapeutics and Tumor Biology (Nonimmuno)
Date and Time: Saturday, June 1, 2019, 8:00 – 11:00 am CT
Location: McCormick Place, Event room: Hall A, 2301 S King Dr, Chicago, Illinois

Title: A Phase 1/2 First-in-Human Trial of Oral SRA737 (a Chk1 inhibitor) Given in Combination with Low Dose Gemcitabine in Subjects with Advanced Cancer.
Abstract: 3095; Poster #: 87
Poster Session: Developmental Therapeutics and Tumor Biology (Nonimmuno)
Date and Time: Saturday, June 1, 2019, 8:00 – 11:00 am CT
Location: McCormick Place, Event room: Hall A, 2301 S King Dr, Chicago, Illinois

The posters will be available on June 1, 2019 on the Sierra Oncology website at www.sierraoncology.com

About SRA737 and SRA737+LDG
SRA737 is a potent, highly selective, orally bioavailable small molecule inhibitor of Checkpoint kinase 1 (Chk1), a key regulator of cell cycle progression and the DNA Damage Response (DDR). Tumors with high levels of replication stress become reliant on Chk1 to mitigate the potentially catastrophic consequences of excess genomic instability.

Intrinsic sources of replication stress can include genetic alterations in tumor suppressors, oncogenes or DNA Damage Repair genes. Tumors harboring defects in these gene classes are hypothesized to have higher levels of intrinsic replication stress due to dysregulated cell cycle control, increased proliferation demands and increased genomic instability. SRA737+LDG is a novel drug combination, where non-cytotoxic low dose gemcitabine (LDG) acts as a potent extrinsic inducer of replication stress.

Sierra Oncology retains the global commercialization rights to SRA737.

On June 1, 2019 Clovis Oncology, Inc. (NASDAQ: CLVS) reported multiple datasets being presented at the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, May 31 – June 4, 2019 (Press release, Clovis Oncology, JUN 1, 2019, View Source [SID1234536750]). These include presentations of exploratory endpoint evaluations and updated safety data from the pivotal Phase 3 ARIEL3 trial evaluating Rubraca (rucaparib) for the maintenance treatment of advanced ovarian cancer, as well as genomic characteristics of BRCA1/2 mutations among metastatic castration-resistant prostate cancer (mCRPC) patients in the Phase 2 TRITON2 trial evaluating Rubraca in mCRPC.

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"The breadth and depth of data from both company and investigator-sponsored Rubraca trials presented at this year’s ASCO (Free ASCO Whitepaper) meeting demonstrate the growing strength of the data and clinical development programs behind Rubraca," said Patrick J. Mahaffy, President and CEO of Clovis Oncology. "Accordingly, we look forward to presenting updated clinical data from the TRITON2 study at an upcoming medical conference in the second half of 2019 and submitting our planned supplemental NDA filing for BRCA-mutant advanced prostate cancer in Q4 2019."

ARIEL3 Exploratory Endpoints and Updated Safety Data

During an afternoon session on Saturday, June 1, Robert L. Coleman, MD, professor of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center in Houston and co-coordinating investigator in the ARIEL3 clinical trial program, will present the poster "Exploratory analysis of the effect of maintenance rucaparib on post-progression outcomes in patients with platinum-sensitive recurrent ovarian carcinoma and updated safety data from the phase 3 study ARIEL3" (Abstract #5522/Poster Board #345).

Data from this analysis of the ARIEL3 trial, which enrolled patients with platinum-sensitive recurrent ovarian carcinoma, demonstrated that Rubraca significantly improved the clinically meaningful exploratory endpoints of chemotherapy-free interval (CFI), time to start of first subsequent therapy (TFST), time to investigator-assessed progression on the subsequent line of treatment or death (PFS2), and time to second subsequent therapy (TSST) vs. placebo.

The updated safety profile generated in this analysis is consistent with the previously-reported primary efficacy data analysis based on a data cutoff date of April 15, 2017. As of December 31, 2017, the most common treatment-emergent adverse events (TEAEs) of any grade (rucaparib vs. placebo) were nausea (75.8% vs. 36.5%), asthenia/fatigue (70.7% vs. 44.4%), dysgeusia (39.8% vs. 6.9%), and anemia/decreased hemoglobin (39.0% vs. 5.3%). The most common grade ≥3 TEAEs were anemia/decreased hemoglobin (21.5% vs. 0.5%) and alanine/aspartate aminotransferase increase (10.2% vs. 0.0%).

"These data positively reinforce our current clinical utilization and understanding of rucaparib as maintenance treatment for women with advanced ovarian cancer," said Dr. Coleman. "They provide further confirmation that rucaparib may help women and their physicians sustain a response to platinum-based chemotherapy."

Genomic Characteristics of BRCA1/2 Alterations in Patients with mCRPC Enrolled in TRITON2

Also on Saturday, June 1, Wassim Abida, MD, Medical Oncologist, Memorial Sloan Kettering Cancer Center, and coordinating investigator for the TRITON2 study, will present the poster "Genomic characteristics of deleterious BRCA1 and BRCA2 alterations and associations with baseline clinical factors in patients with metastatic castration-resistant prostate cancer (mCRPC) enrolled in TRITON2" (Abstract #5031/Poster Board #143).

The ongoing phase 2 TRITON2 (NCT02952534) study is evaluating the poly(ADP-ribose) polymerase inhibitor rucaparib in mCRPC patients harboring a deleterious germline or somatic mutation in BRCA1, BRCA2, ATM, or other DNA damage repair (DDR) genes as determined by central screening of tumor tissue or plasma, or from local testing. Next-generation sequencing (NGS) assays evaluating tumor tissue and circulating cell-free tumor DNA (ctDNA) in plasma were both used to successfully identify patients with eligible alterations in BRCA1/2. The plasma assay is minimally invasive and reliably detects alterations in patients with disease that is difficult to biopsy.

In this analysis, associations between baseline genomic and clinical characteristics were assessed. Several findings support the hypothesis that germline BRCA1/2 alterations are a prognostic factor in prostate cancer associated with more rapid progression to advanced disease. Patients with germline BRCA1/2 alterations were younger at time of enrollment into TRITON2, had more advanced disease at time of diagnosis and had a shorter time between diagnosis and enrollment into TRITON2 as compared to patients with somatic BRCA1/2 alterations. However, responses to rucaparib were observed in patients with germline or somatic BRCA1/2 alterations, highlighting the potential of rucaparib to benefit both groups of patients.

Today’s poster includes the confirmed objective response rate (ORR) data based on the same June 29, 2018 visit cut-off date presented at ESMO (Free ESMO Whitepaper) 2018 and presents those data by germline or somatic BRCA1/2 mutation status. By investigator-assessed RECIST/PCWG3, the confirmed ORR in patients with a germline or somatic BRCA1/2 mutation treated with Rubraca was 50% (5/10) or 40% (6/15), respectively. By PSA response, the confirmed ORR in patients with a germline or somatic BRCA1/2 mutation treated with Rubraca was 66.7% (10/15) or 43.3% (13/30), respectively.

"These data reinforce the importance of genomic testing to inform clinical decision making, including consideration of plasma testing in patients with mCRPC," said Dr. Abida. "Clinicians are increasingly reliant on a patient’s unique genomic profile to determine therapeutic options, especially as targeted agents such as PARP inhibitors advance toward additional approved indications."

The Clovis-sponsored ASCO (Free ASCO Whitepaper) posters will be available online at View Source as of the time they are presented at the meeting.

Additional Rubraca Poster Presentations: Investigator-Initiated Trials

Two trials in progress posters describe investigator-initiated studies that were selected for poster presentations at the 2019 ASCO (Free ASCO Whitepaper) Annual Meeting. These include a multi-center Phase 2 trial of rucaparib in combination with nivolumab as maintenance therapy for patients with advanced biliary tract cancer (Abstract #TPS4153/Poster Board #252a) to be presented on Monday, June 3 from 8:00-11:00am CDT in Hall A; and a Phase 1b/2a study of rucaparib combined with nivolumab in mCRPC and advanced/recurrent endometrial cancer (Abstract #TPS2663/Poster Board #297b) presented today from 8:00-11:00am CDT in Hall A.

About the ARIEL3 Clinical Trial

The ARIEL3 pivotal study of rucaparib is a confirmatory randomized, double-blind study comparing the effects of rucaparib against placebo to evaluate whether rucaparib given as a maintenance treatment to platinum-sensitive ovarian cancer patients can extend the period of time for which the disease is controlled after a complete or partial response to platinum-based chemotherapy. The study enrolled 564 patients with high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer. To be eligible for the study, participants had to have received at least two prior platinum-based treatment regimens, been sensitive to the penultimate platinum regimen, and achieved a complete or partial response to their most recent platinum-based regimen. There were no genomic selection criteria for this study. Trial participants were randomized 2:1 to receive 600 milligrams of rucaparib twice daily (BID) or placebo. The study achieved its primary endpoint of improved PFS by investigator review in each of three populations. PFS was also improved in the rucaparib group compared with placebo by independent review, a key secondary endpoint, in all three populations. In addition, rucaparib improved objective response rate vs. placebo among evaluable trial participants in all three study populations.

About the TRITON2 Clinical Trial

TRITON2 is an international, multicenter, open-label Phase 2 study of Rubraca in men with metastatic castration-resistant prostate cancer with BRCA gene alterations (inclusive of germline or somatic), which is also enrolling patients with deleterious alterations of other DNA damage repair (DDR) genes, including ATM. The study is currently enrolling across sites worldwide. For more information, please visit www.tritontrials.com.

About Rubraca (rucaparib)

Rucaparib is an oral, small molecule inhibitor of PARP1, PARP2 and PARP3 being developed in multiple tumor types, including ovarian and metastatic castration-resistant prostate cancers, as monotherapy, and in combination with other anti-cancer agents. Exploratory studies in other tumor types are also underway.

Clovis holds worldwide rights for Rubraca. Rubraca is an unlicensed medical product outside of the U.S. and the EU.

Rubraca U.S. FDA Approved Indications and Important Safety Information

Rubraca is indicated as monotherapy for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.

Rubraca is indicated as monotherapy for the treatment of adult patients with deleterious BRCA mutations (germline and/or somatic) associated epithelial ovarian, fallopian tube, or primary peritoneal cancer who have been treated with two or more chemotherapies and selected for therapy based on an FDA-approved companion diagnostic for Rubraca.

Select Important Safety Information

Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML) occur uncommonly in patients treated with Rubraca, and are potentially fatal adverse reactions. In approximately 1,100 treated patients, MDS/AML occurred in 12 patients (1.1%), including those in long-term follow-up. Of these, five occurred during treatment or during the 28-day safety follow-up (0.5%). The duration of Rubraca treatment prior to the diagnosis of MDS/AML ranged from 1 month to approximately 28 months. The cases were typical of secondary MDS/cancer therapy-related AML; in all cases, patients had received previous platinum-containing regimens and/or other DNA-damaging agents. Do not start Rubraca until patients have recovered from hematological toxicity caused by previous chemotherapy (≤ Grade 1).

Monitor complete blood counts for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities (> 4 weeks), interrupt Rubraca or reduce dose (see Dosage and Administration [2.2] in full Prescribing Information) and monitor blood counts weekly until recovery. If the levels have not recovered to Grade 1 or less after 4 weeks, or if MDS/AML is suspected, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample cytogenetic analysis. If MDS/AML is confirmed, discontinue Rubraca.

Based on its mechanism of action and findings from animal studies, Rubraca can cause fetal harm when administered to a pregnant woman. Apprise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of Rubraca.

Most common adverse reactions in ARIEL3 (≥ 20%; Grade 1–4) were nausea (76%), fatigue/asthenia (73%), abdominal pain/distention (46%), rash (43%), dysgeusia (40%), anemia (39%), AST/ALT elevation (38%), constipation (37%), vomiting (37%), diarrhea (32%), thrombocytopenia (29%), nasopharyngitis/upper respiratory tract infection (29%), stomatitis (28%), decreased appetite (23%) and neutropenia (20%).

Most common laboratory abnormalities in ARIEL3 (≥ 25%; Grade 1–4) were increase in creatinine (98%), decrease in hemoglobin (88%), increase in cholesterol (84%), increase in alanine aminotransferase (ALT) (73%), increase in aspartate aminotransferase (AST) (61%), decrease in platelets (44%), decrease in leukocytes (44%), decrease in neutrophils (38%), increase in alkaline phosphatase (37%) and decrease in lymphocytes (29%).

Most common adverse reactions in Study 10 and ARIEL2 (≥ 20%; Grade 1–4) were nausea (77%), asthenia/fatigue (77%), vomiting (46%), anemia (44%), constipation (40%), dysgeusia (39%), decreased appetite (39%), diarrhea (34%), abdominal pain (32%), dyspnea (21%) and thrombocytopenia (21%).

Most common laboratory abnormalities in Study 10 and ARIEL2 (≥ 35%; Grade 1–4) were increase in creatinine (92%), increase in alanine aminotransferase (ALT) (74%), increase in aspartate aminotransferase (AST) (73%), decrease in hemoglobin (67%), decrease in lymphocytes (45%), increase in cholesterol (40%), decrease in platelets (39%) and decrease in absolute neutrophil count (35%).

Co-administration of Rubraca can increase the systemic exposure of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, which may increase the risk of toxicities of these drugs. Adjust dosage of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, if clinically indicated. If co-administration with warfarin (a CYP2C9 substrate) cannot be avoided, consider increasing frequency of international normalized ratio (INR) monitoring. Because of the potential for serious adverse reactions in breast-fed children from Rubraca, advise lactating women not to breastfeed during treatment with Rubraca and for 2 weeks after the last dose. You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Clovis Oncology, Inc. at 1-844-258-7662.

Click here for full Prescribing Information and additional Important Safety Information.

Rubraca (rucaparib) EU Authorized Use and Important Safety Information

Rucaparib is indicated as monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy.

Rucaparib is indicated as monotherapy treatment of adult patients with platinum sensitive, relapsed or progressive, BRCA mutated (germline and/or somatic), high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have been treated with two or more prior lines of platinum-based chemotherapy, and who are unable to tolerate further platinum-based chemotherapy.

Summary warnings and precautions: Haematological toxicity: Patients should not start Rubraca until they have recovered from haematological toxicities caused by previous chemotherapy (≤ CTCAE Grade 1). Complete blood count testing prior to starting treatment with Rubraca and monthly thereafter is advised. Rubraca should be interrupted or dose reduced and blood counts monitored weekly until recovery for the management of low blood counts. Myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML): If MDS/AML is suspected, the patient should be referred to a haematologist for further investigation. If MDS/AML is confirmed, Rubraca should be discontinued. Photosensitivity: Patients should avoid spending time in direct sunlight as they may burn more easily. When outdoors, patients should wear protective clothing and sunscreen with SPF of 50 or greater. Gastrointestinal toxicities: Low grade (CTCAE Grade 1 or 2) nausea and vomiting may be managed with dose reduction or interruption. Additionally, antiemetics may be considered for treatment or prophylaxis.

Click here to access the current Summary of Product Characteristics. Healthcare professionals should report any suspected adverse reactions via their national reporting systems.

On June 1, 2019 Veracyte, Inc. (Nasdaq: VCYT) reported new data demonstrating the potential for its Afirma Xpression Atlas (XA) genomic test to guide targeted treatment selection for patients with a rare but aggressive form of thyroid cancer concurrent with diagnosis by the company’s Afirma Genomic Sequencing Classifier (GSC) (Press release, Veracyte, JUN 1, 2019, View Source [SID1234536766]).

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The findings advance physicians’ ability to answer multiple clinical questions for their thyroid patients using a single, minimally invasive sample. They were presented today at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, which is being held May 31-June 4, 2019 in Chicago.

Researchers used the Afirma XA to conduct RNA sequencing on 90 thyroid fine needle aspiration samples that had been diagnosed with medullary thyroid cancer (MTC) through the Afirma GSC. The cohort was derived from nearly 30,000 sequential samples that were indeterminate or suspicious for cancer following traditional cytopathology testing. The researchers found that the Afirma XA identified a gene variant or fusion in 74 percent of the MTC cases and that 99 percent of these cases had one or more variants or fusions – RET, KRAS, HRAS and/or BRAF alterations – that are targeted by new therapies that are currently in clinical trials or early stage development.

"With the emergence of new molecularly targeted therapies for medullary thyroid cancer, molecular testing to identify the driver genomic mutations will be key to optimizing patient outcomes," said Lori J. Wirth, M.D., medical director of the Center for Head and Neck Cancers at Massachusetts General Hospital, who presented the findings in a poster session today. "The potential to select targeted therapy at the time of diagnosis may be especially helpful for patients with advanced disease."

The Afirma GSC and Xpression Atlas provide physicians with a comprehensive solution for a complex landscape in thyroid nodule diagnosis and individualization of care. Veracyte developed the Afirma GSC with RNA whole-transcriptome sequencing and machine learning. The test helps identify patients with benign thyroid nodules among those with indeterminate cytopathology results in order to help patients avoid unnecessary diagnostic thyroid surgery, while also identifying patients with MTC. The Afirma XA provides physicians with genomic alteration content from the same fine needle aspiration samples that are used in Afirma GSC testing and may help physicians decide with greater confidence on the surgical or therapeutic pathway for their patients. The Afirma XA includes 761 DNA variants and 130 RNA fusion partners in over 500 genes that are associated with thyroid cancer.

"These new data show that our comprehensive Afirma solution can not only help patients avoid unnecessary diagnostic surgery when their nodules are benign, but may also inform targeted therapy selection when thyroid cancer is diagnosed," said Bonnie Anderson, Veracyte’s chairman and chief executive officer. "These findings represent a significant step forward in delivering on the promise of precision medicine for thyroid cancer patients."

About Thyroid Cancer

The American Cancer Society estimates that 54,070 people in the United States will be diagnosed with thyroid cancer this year. Medullary thyroid cancer, which is more difficult to find and treat, makes up approximately 4 percent of all thyroid cancers. Each year in the United States approximately 525,000 patients undergo FNA biopsies to evaluate thyroid nodules for cancer. Up to 30 percent of these patients receive indeterminate results – meaning they are not clearly benign or malignant – and, historically, most were directed to diagnostic surgery even though 70 percent to 80 percent of the time the nodules ultimately proved to be benign.