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Kite Pharma Announces the First Meta-Analysis of Outcomes in Chemorefractory Diffuse Large B-Cell Lymphoma (SCHOLAR-1)

On June 6, 2016 Kite Pharma, Inc. (Nasdaq:KITE) ("Kite") reported results from SCHOLAR-1 (Retrospective Non-Hodgkin Lymphoma Research), the first, large, systematic, multi-institutional, patient-level meta-analysis of outcomes from 635 patients with chemorefractory diffuse large B-cell lymphoma (DLBCL) (Press release, Kite Pharma, JUN 6, 2016, View Source [SID:1234513046]). The study showed that patients with chemorefractory disease – defined as disease that does not respond to treatment with a chemotherapy-based regimen or has relapsed less than 12 months after autologous stem cell transplant (ASCT) – have consistently poor outcomes regardless of refractory subgroup, line of therapy, and disease stage. The study will be presented today at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (abstract #7516).

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"These study results are important because they confirm the regrettable outcomes that have been observed in the clinical setting for people with this difficult-to-treat form of DLBCL," said Dr. John Kuruvilla, Associate Professor of Medicine at the University of Toronto, and a clinical investigator in the Department of Medical Oncology at Princess Margaret Cancer Centre in Toronto. "While DLBCL is considered curable with initial chemotherapy-based treatment, patients with chemorefractory DLBCL have limited-to-no treatment options and historically poor outcomes, underscoring the significant need for new therapies."

According to the American Cancer Society, non-Hodgkin lymphoma (NHL) accounts for about four percent of all cancers in the United States, making it one of the most common cancers diagnosed. DLBCL is the most common form of the disease, accounting for one out of every three cases of NHL.1 It is estimated that approximately 26,000 people will be diagnosed with DLBCL in the United States in 2016.

"Little is known about the outcomes of people with chemorefractory DLBCL, leaving a large gap in the treatment landscape. These data help to track the course of the disease and provide an important historical benchmark for studies in this patient population," said David Chang, M.D., Ph.D., Kite’s Executive Vice President, Research and Development, and Chief Medical Officer. "We are proud to partner with clinicians, scientists and researchers at MD Anderson Cancer Center, the Mayo Clinic, the University of Iowa, the Canadian Cancer Trials Group, and LYSARC (The Lymphoma Academic Research Organisation) to help establish a better understanding of the disease to determine how best to treat patients with chemorefractory DLBCL."

About the SCHOLAR-1 Study

The SCHOLAR-1 (Retrospective Non-Hodgkin Lymphoma Research) is a retrospective analysis of patients with chemorefractory DLBCL comprised of data from Phase 3 studies from the Canadian Cancer Trials Group (CCTG LY.12 Study) and LYSARC (CORAL Study) and large retrospective databases including from the MD Anderson Cancer Center, Mayo Clinic and University of Iowa Specialized Programs of Research Excellence (SPORE).

In the study, 635 patients with chemorefractory DLBCL were eligible for evaluation based on the following criteria: DLBCL defined as progressive disease as best response to chemotherapy; or stable disease as best response to chemotherapy (received at least 4 cycles of first-line or 2 cycles of later-line therapy); or relapse ≤ 12 months of ASCT. Patients must have received an anti-CD20 monoclonal antibody (unless CD20 negative) and an anthracycline as one of their prior regimens.

Results to be presented at ASCO (Free ASCO Whitepaper) showed:

The overall response rate (ORR; complete response plus partial response) across all 635 patients was 26% (165/635) with only 8% (51/635) achieving a complete response, showing no signs of the disease
The response rates were consistent ranging from 21% to 31% ORR and 2% to 15% complete response (CR) across centers and data sets
Median overall survival was 6.6 months and consistent across subgroups including refractory status, stage of disease and line of therapy

Data From a Study Utilizing FoundationOne® Heme Indicates Age-Associated Genomic Profiles in Acute Myeloid Leukemia

On June 6, 2016 Foundation Medicine, Inc. (NASDAQ:FMI) reported new data informed by comprehensive genomic profiling (CGP) using FoundationOne Heme demonstrating the diverse and distinct genomic landscape of acute myeloid leukemia (AML) in children versus adults (Press release, Foundation Medicine, JUN 6, 2016, View Source [SID:1234513044]). Foundation Medicine conducted comprehensive genomic profiling of tumor samples from 558 patients with AML, including 104 pediatric and 454 adult patients, and identified age-associated genomic alterations in a subset of patients that could influence and personalize treatment and inform the selection of approved targeted therapies or access to novel therapies available in clinical trials.

In collaboration with the Children’s Oncology Group AML Disease Committee, a clinical trials group supported by the National Cancer Institute (NCI), cases with known cytogenetic and molecular aberrations underwent CGP with FoundationOne Heme. The results demonstrated 100% concordance between FoundationOne Heme and conventional biomarker analysis across the various cytogenetic hallmarks of AML, including changes to inv(16) and t(8;21), as well as DNA mutations including FLT3/ITD, NPM1, and CEBPA. Importantly, FoundationOne Heme identified multiple additional mutations, such as structural alterations and copy number variations, including alterations that have therapeutic significance. These results suggest the potential clinical benefit of FoundationOne Heme in AML as compared to single gene or hotspot-based clinical testing, and underscore FoundationOne Heme’s unique capability to enhance risk stratification and identify molecular targets for therapeutic intervention.

The data showed a clear age-associated profile with distinct genomic make-up in pediatric versus adult patients. Novel transcripts such as NSD1-NUP98, KDM5A-NUP98 and CBFA2T3-GLIS2 were identified in 21 patients, 16 of whom were children. Fusions were markedly enriched in pediatric patients, while mutations in epigenetic modifiers occurred almost exclusively in adults, including DNMT3A (22 percent), IDH1/2 (21 percent) and TET2 (15 percent). Mutations in ASXL1 (21 percent), SRSF2 (14 percent) and BCOR (9 percent) were also prevalent in adults, but rare in children (0-6%).

"Like many blood cancers, AML is characterized by recurring genomic alterations that often provide information about disease progression and outcome, making comprehensive genomic profiling incredibly important to informing diagnosis and therapeutic decisions," said Vincent Miller, M.D., chief medical officer, Foundation Medicine. "Recognizing that there are fundamental differences between the genomic alterations in pediatric versus adult AML patients will ultimately arm clinicians with additional information to better understand each patient’s disease and guide therapeutic regimens best suited to a particular age group. We believe these data further support integration of FoundationOne Heme into oncology clinical practice."

The findings were presented in a poster titled, "Distinct Age-Associated Genomic Profiles Identified in Acute Myeloid Leukemia (AML) Using FoundationOne Heme," by Katherine Tarlock, M.D., pediatric hematology-oncology faculty at Seattle Children’s Hospital, and a member of the Children’s Oncology Group AML Committee. The data were presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting 2016 taking place June 3-7 in Chicago.

FoundationOne Heme, an integrated DNA/RNA platform using targeted hybrid-capture next-generation sequencing, is a comprehensive genomic profile developed to detect all types of genomic alterations with therapeutic relevance, including single-nucleotide substitutions, insertions and deletions, copy number alterations and rearrangements, which are not fully evaluated using conventional diagnostic assays. FoundationOne Heme simultaneously detects all classes of genomic alterations in the DNA of 405 cancer-related genes and employs RNA sequencing across 265 genes to capture a broad range of gene fusions, a type of alteration that is a common driver of hematologic cancers. It is designed to provide physicians with clinically actionable information to guide treatment options for patients based on the genomic profile of their cancer.

About Foundation Medicine

Foundation Medicine (NASDAQ:FMI) is a molecular information company dedicated to a transformation in cancer care in which treatment is informed by a deep understanding of the genomic changes that contribute to each patient’s unique cancer. The company offers a full suite of comprehensive genomic profiling assays to identify the molecular alterations in a patient’s cancer and match them with relevant targeted therapies, immunotherapies and clinical trials. Foundation Medicine’s molecular information platform aims to improve day-to-day care for patients by serving the needs of clinicians, academic researchers and drug developers to help advance the science of molecular medicine in cancer. For more information, please visit View Source or follow Foundation Medicine on Twitter (@FoundationATCG).

DelMar Pharmaceuticals Presents Phase I/II GBM Clinical Trial Data and Outlines Future Clinical Development Plans at ASCO 2016 Annual Meeting

On June 6, 2016 DelMar Pharmaceuticals, Inc. (OTCQX: DMPID) ("DelMar" and the "Company"), a company focused on developing and commercializing proven cancer therapies in new orphan drug indications, reported new data from its recently completed Phase I/II clinical trial of VAL-083 (dianhydrogalactitol) at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper)’s (ASCO) (Free ASCO Whitepaper) Annual Meeting on Saturday, June 4, 2016 (Press release, DelMar Pharmaceuticals, JUN 6, 2016, View Source [SID:1234513039]).

"This year’s ASCO (Free ASCO Whitepaper) meeting was an opportunity to share the aggregate of our research to date with the global cancer research community," stated Jeffrey Bacha, chairman and CEO of DelMar Pharmaceuticals. "Based on our findings related to VAL-083’s unique mechanism of action and data from our Phase I/II clinical trial we believe that VAL-083 has the potential to offer a new treatment option for cancer patients whose tumors exhibit features correlated with resistance to currently available chemotherapy."

DelMar’s abstract entitled, "Phase I/II Study of Dianhydrogalactitol in Patients with Recurrent Glioblastoma", was presented during the Central Nervous System poster session on Saturday. The poster presentation can be viewed on DelMar’s website.

In summary, DelMar’s presentation noted:

VAL-083 attacks cancer cells via a unique mechanism of action which is distinct from other chemotherapies used in the treatment of glioblastoma multiforme (GBM). Specifically, VAL-083 is active independent of MGMT, a DNA repair enzyme which is highly expressed in approximately 2/3 of GBM patients and correlated with resistance to temozolomide, the current front-line chemotherapy in the treatment of GBM. Of patients tested in the DelMar trial, 84% exhibited high MGMT.
Median survival of 22 patients receiving an assumed therapeutic dose of VAL-083 (≥20mg/m2) was 8.35 months, suggesting that VAL-083 may offer improved survival for GBM patients following bevacizumab (Avastin) failure in comparison to currently available salvage therapy. Median survival for VAL-083 treated patients following bevacizumab failure compared with published literature demonstrating survival of approximately three to five months with common salvage therapy regimens.
VAL-083 compared to published literature

Reference
Post Avastin
Salvage Therapy
Median Survival from
Bevacizumab Failure

Rahman (2014)
nitrosourea
4.3 months

Mikkelson (2011)
TMZ + irinotecan
4.5 months

Lu (2011)
dasatinib
2.6 months

Reardon (2011)
etoposide
4.7 months

Reardon (2011)
TMZ
2.9 months

Iwomoto (2009)
various
5.1 months

DelMar Trial
VAL-083
8.35 months

A dose of 40 mg/m2/day VAL-083 administered on the first three days of every three week cycle is well tolerated in refractory GBM patients and has been selected for study in subsequent clinical trials.
DelMar recently announced the completion of a successful end of Phase II meeting with the US FDA and its plans to advance VAL-083 into a pivotal clinical trial for GBM patients whose tumors have recurred following front-line therapy and second line treatment with bevacizumab.

DelMar’s advanced development program will feature a single randomized Phase 3 study measuring survival outcomes compared to a "physicians’ choice" control, which, if successful, would serve as the basis for a New Drug Application (NDA) submission for VAL-083. The control arm will consist of a limited number of salvage chemotherapies currently utilized in the treatment of Avastin-failed GBM. The final pivotal trial design will be confirmed with the FDA following further discussions with the Company’s clinical advisors.

In addition to the pivotal trial, DelMar also plans to initiate two separate Phase II clinical trials in earlier-stage GBM patients.

A randomized, non-comparative, biomarker-driven, Phase 2 study to determine if treatment of MGMT-unmethylated recurrent GBM with VAL-083 or CCNU improves overall survival at 9 months, compared to historical control in bevacizumab naïve patients. (clinicaltrials.gov identifier: NCT02717962)
A single arm Phase 2 clinical trial to confirm the tolerability of DelMar’s dosing regimen in combination with radiotherapy (XRT) and to explore the activity of VAL-083 in newly diagnosed MGMT-unmethylated GBM patients whose tumors are known to express high levels of MGMT.
"We wish to thank the patients, their families, and the physicians who participated in our Phase I/II clinical trial," said Mr. Bacha. "We are pleased to be advancing VAL-083 into these new trials that we believe, if successful, will serve as the basis for a new treatment paradigm in the treatment of GBM."

About VAL-083
VAL-083 is a "first-in-class," small-molecule chemotherapeutic. In more than 40 Phase I and II clinical studies sponsored by the U.S. National Cancer Institute, VAL-083 demonstrated clinical activity against a range of cancers including lung, brain, cervical, ovarian tumors and leukemia both as a single-agent and in combination with other treatments. VAL-083 is approved in China for the treatment of chronic myelogenous leukemia (CML) and lung cancer, and has received orphan drug designation in Europe and the U.S. for the treatment of malignant gliomas. DelMar recently announced that the USFDA’s Office of Orphan Products had also granted an orphan designation to VAL-083 for the treatment of medulloblastoma.

DelMar has demonstrated that VAL-083’s anti-tumor activity is unaffected by the expression of MGMT, a DNA repair enzyme that is implicated in chemotherapy resistance and poor outcomes in GBM patients following standard front-line treatment with Temodar (temozolomide).

DelMar conducted a Phase I/II clinical trial in GBM patients whose tumors have progressed following standard treatment with temozolomide, radiotherapy, bevacizumab and a range of salvage therapies. Patients were enrolled at five clinical centers in the United States: Mayo Clinic (Rochester, MN); UCSF (San Francisco, CA) and three centers associated with the Sarah Cannon Cancer Research Institute (Nashville, TN, Sarasota, FL and Denver, CO) (clinicaltrials.gov identifier: NCT01478178). DelMar announced the completion of enrollment in a Phase II expansion cohort in September, 2015.

About Glioblastoma Multiforme (GBM)
Glioblastoma multiforme (GBM) is the most common and most malignant form of brain cancer. Approximately 15,000 people are diagnosed with GBM each year in the U.S., with similar incidence in Europe. Standard of care is surgery, followed by either radiation therapy, or radiation therapy combined with temozolomide. Approximately 60 percent of GBM patients treated with temozolomide experience tumor progression within one year. More than half of glioblastoma patients will fail the currently approved therapies and face a very poor prognosis.

CytRx Presents Updated Aldoxorubicin Clinical Trial Results at the 2016 American Society of Clinical Oncology Annual Meeting

On June 6, 2016 CytRx Corporation (NASDAQ: CYTR), a biopharmaceutical research and development company specializing in oncology, reported the presentation of three posters featuring updated clinical data from its aldoxorubicin clinical trials at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting being held June 3-7, 2016, at McCormick Place in Chicago (Press release, CytRx, JUN 6, 2016, View Source;p=RssLanding&cat=news&id=2175339 [SID:1234513038]).

"The clinical data presented this year at ASCO (Free ASCO Whitepaper) continues to support the safety and activity of aldoxorubicin in multiple high unmet need tumor types, including in late-stage and heavily pre-treated patients," commented Daniel Levitt, M.D., Ph.D., CytRx’s Executive Vice President and Chief Medical Officer. "With over 550 cancer patients treated with aldoxorubicin to date, oncologists are becoming comfortable with the safety and utility profile of the drug."

The details for the ASCO (Free ASCO Whitepaper) 2016 poster presentations are as follows:

Title: Phase 2 study of aldoxorubicin in relapsed glioblastoma
Date/Time: June 4, 2016 1:00pm-5:00pm
Poster Session: Central Nervous System Tumors; Abstract 2027
Summary: This ongoing Phase 2 clinical trial is evaluating aldoxorubicin in patients with relapsed glioblastoma (GBM). Twenty-eight patients who had prior treatment with surgery, radiation and temozolomide therapy were enrolled and received either 250mg/m2 or 350mg/m2 of aldoxorubicin once every three weeks. To date, aldoxorubicin has demonstrated anti-tumor activity and appears to be relatively well-tolerated with patients receiving a median of 3 or 4 cycles (range 1-20) depending on the dose group. No evidence of central nervous system toxicity or clinically significant cardiac toxicity has been observed. Best responses in 21 subjects according to MRI were 3 patients with partial response (PR) and 7 patients with stable disease (SD). Additionally, two patients underwent surgery following aldoxorubicin treatment, and the pathology analysis of the removed tissue showed no viable tumor. The median overall survival was 8.6 months (95% CI: 7.8-10.1) with seven patients still on study and being followed.

This study provides the first evidence that aldoxorubicin’s albumin-binding mechanism allows it to cross the blood-brain barrier, unlike doxorubicin, and kill glioblastoma cells. Following the completion of this trial, CytRx will evaluate the clinical path forward for aldoxorubicin as a treatment for advanced GBM.

Title: Phase 1b study of aldoxorubicin + gemcitabine in metastatic solid tumors
Date/Time: June 5, 2016 8:00am-11:30am
Poster Session: Developmental Therapeutics – Clinical Pharmacology and Experimental Therapeutics; Abstract: 2523
Summary: This ongoing Phase 1b study is evaluating aldoxorubicin in combination with gemcitabine in patients with metastatic solid tumors. To date, 29 heavily pre-treated patients (median prior regimens 3-4; range 0-15) have been enrolled in four different dose combination cohorts. Of 18 evaluable patients, 13 of 18 (72%) had clinical benefit including two partial responses and 11 patients with stable disease. The confirmed partial responses were in a patient with ovarian cancer and a patient with uterine leiomyosarcoma. Across all dose groups the number of completed cycles range from 1-17, and cumulative doxorubicin exposure ranges from 208mg to 4,103mg. Doses of 200 mg/m2 aldoxorubicin with 500 mg/m2 gemcitabine appears to be best tolerated. Patients continue to be treated in the final dose cohort.

Although patients in this trial had a variety of different types of cancer, the future focus of this combination will be the treatment of ovarian and endometrial adenocarcinoma.

Title: Treatment of HIV-associated Kaposi’s sarcoma with aldoxorubicin
Date/Time: June 6, 2016 8:00am-11:30am
Poster Session: Sarcoma; Abstract: 11038
Summary: This ongoing open-label Phase 2 clinical trial is evaluating the efficacy and safety of low dose aldoxorubicin for the treatment of Kaposi’s sarcoma (KS) in HIV-infected patients. Fifteen patients have been enrolled and received either 50, 100, or 150 mg/m2 of aldoxorubicin once every three weeks. To date, significant anti-tumor activity has been observed. At these low doses, 11 of 13 (85%) patients have achieved partial responses at cycle 4, and at the end of the study, 8 of 12 (67%) patients have demonstrated partial responses. Two patients continue to be treated. Aldoxorubicin was very well-tolerated in these patients with advanced Kaposi’s sarcoma due to the low doses administered. Importantly, determining the drug concentration within the tumor, a key goal of the trial, was successfully achieved. In 12 of 14 (86%) patients for whom there was adequate tissue for analysis, higher doxorubicin concentrations were detected within the KS lesion relative to non-tumor tissue.

The high level of activity and important tolerability of low dose aldoxorubicin will allow long term usage in this very difficult to treat group of patients.

About Aldoxorubicin
The widely used chemotherapeutic agent doxorubicin is delivered systemically and is highly toxic, which limits its dose to a level below its maximum therapeutic benefit. Doxorubicin also is associated with many side effects, especially the potential for damage to heart muscle at cumulative doses greater than 450 mg/m2. Aldoxorubicin combines doxorubicin with a novel single-molecule linker that binds directly and specifically to circulating albumin, the most plentiful protein in the bloodstream. Protein-hungry tumors concentrate albumin, thus increasing the delivery of the linker molecule with the attached doxorubicin to tumor sites. In the acidic environment of the tumor, but not the neutral environment of healthy tissues, doxorubicin is released. This allows for greater doses (3 ½ to 4 times) of doxorubicin to be administered while reducing its toxic side effects. In studies thus far there has been no evidence of clinically significant effects of aldoxorubicin on heart muscle, even at cumulative doses of drug well in excess of 2,000 mg/m2.

Cyclacel Reports Updated Data From Its DNA Damage Response Program on Seliciclib and Sapacitabine Combination in Patients With Solid Tumors at ASCO

On June 06, 2016 Cyclacel Pharmaceuticals, Inc. (NASDAQ:CYCC) (NASDAQ:CYCCP) (Cyclacel or the Company), reported updated Phase 1 data from its DNA damage response program evaluating a combination regimen of two Cyclacel product candidates, seliciclib, a cyclin dependent kinase (CDK) inhibitor, and sapacitabine, a nucleoside analogue (Press release, Cyclacel, JUN 6, 2016, View Source [SID:1234513037]). The regimen was orally-administered as sequential (Part 1) or concomitant (Part 2) treatment to 67 heavily-pretreated patients with advanced solid tumors. Antitumor activity was demonstrated in a subgroup of 45 patients with breast, ovarian and pancreatic cancers who tested positive for BRCA mutations (44 germline and 1 sporadic) with a 35.6% disease control rate (1 CR, 5 PR and 10 SD). Treatment durations in responders ranged between 16 and over 240 weeks. No CR or PR was observed in BRCA negative patients. Data were presented at an oral presentation at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago.

"We are encouraged by the durable responses and stable disease seen with the seliciclib and sapacitabine combination in patients with BRCA mutations, in particular because most were heavily pretreated and many are able to remain on study for extended periods," said Sara M. Tolaney, M.D., M.P.H., Associate Director, Clinical Research, Breast Oncology, Dana-Farber Cancer Institute, Boston. "Our findings from Parts 1 and 2 of the study have shown that the orally-administered regimen is well tolerated with manageable toxicities. Based on the results, we believe that further clinical evaluation of this combination regimen is warranted. A Part 3 extension of the study is currently enrolling advanced breast cancer patients with BRCA mutations."

"The findings reported in Dr. Tolaney’s presentation show that the combination treatment of seliciclib and sapacitabine is active and tolerable," said Judy Chiao, M.D., Vice President, Clinical Development and Regulatory Affairs of Cyclacel. "This clinical observation may be directly related to the drugs interference with the capacity of BRCA-mutated cancer cells to repair and survive sapacitabine-induced breaks in their DNA. If these preliminary findings are confirmed by further data, this regimen may provide an important treatment option for patients with BRCA-mutated cancers."

"The ASCO (Free ASCO Whitepaper) data build on earlier data from our DNA damage response program highlighted by the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting Program Committee in a 2013 press conference," said Spiro Rombotis, President and Chief Executive Officer of Cyclacel. "The updated data support and extend clinical evidence of efficacy with different schedules of the combination in this patient population. We are encouraged with the durability of responses and stable disease, with ongoing responding patients achieving treatment durations exceeding 1 and 4.5 years respectively. We look forward to reporting data from the ongoing Part 3 extension in BRCA positive patients with breast cancer and increasing our understanding of the potential benefits of this differentiated treatment strategy in a targeted patient population with significant unmet medical need."

Results

The trial is a dose escalation study conducted in patients with advanced and incurable solid tumors. The orally-administered regimen consists of sapacitabine administered twice daily for 7 days sequentially followed by seliciclib twice daily for 3 days over a 21 day cycle (Part 1, n=38); and sapacitabine dosed each morning followed by seliciclib each evening, each once daily for 5 days per week for 2 weeks of a 28 day cycle (Part 2, n=29). The primary objective of the trial is to determine the maximum tolerated dose with a secondary objective of antitumor activity of the combination. Sixty-seven patients have been treated in Parts 1 and 2 of the study, of which 44 were found to carry BRCA mutations and one a sporadic BRCA mutation.

Best Responses

PART 1 PART 2
BRCA carriers Others BRCA carriers Others
(n=16) (n=22) (n= 28) (n=1)
CR 1 - - -
PR 3 - 2 -
SD 2 6 7 1*
ORR (CR/PR) 25 % 0 % 7 % 0 %
Disease Control (CR/PR/SD) 6 (37.5%) 6 (27.3%) 9 (32.1%) 1 (100.0 %)

* One patient had a sporadic BRCA mutation. CR=complete response, PR=partial response, SD=stable disease.

One CR and five PR were observed in BRCA mutation carriers with breast, ovarian and pancreatic cancers. Treatment durations for the 3 breast/ovarian cancer responders in Part 1 are 54, 93, over 240 weeks and the one breast cancer responder in Part 2 over 76 weeks respectively. Treatment durations for the two pancreatic cancer responders, one each in Parts 1 and 2, are 21 and 16 weeks respectively. Responders included patients who underwent prior treatment with PARP inhibitors and PARP naïve patients. SD was observed in 9 BRCA mutation carriers and 1 sporadic BRCA positive patient with treatment durations ranging from 16 to 88 weeks.

Overall in BRCA positive patients (Parts 1 and 2, n=45), disease control rate is 35.6% and overall response rate (ORR) is 11% (Part 1 ORR 25% and Part 2 7%). The difference in Part 1 and Part 2 ORRs may suggest that the seliciclib dose in the Part 2 schedule may be too low for enhancing the activity of sapacitabine.

Pharmacodynamic effects of the seliciclib and sapacitabine combination were observed in skin biopsies. Part 1 biopsies following treatment showed a 2.3-fold increase in DNA damage induced by sapacitabine, as measured by gamma-H2AX immunohistochemistry. Additional DNA damage occurred after treatment with seliciclib with a 0.58-fold further increase in gamma-H2AX staining.

In Part 1 recommended Phase 2 doses (RP2D) are: sapacitabine 50 mg b.i.d./seliciclib 800 mg b.i.d. Most frequent grade 3/4 adverse events were neutropenia (16%) and elevation in AST (16%). In Part 2 RP2D are: sapacitabine 250 mg q.d./seliciclib 200 mg q.d. Most frequent grade 3/4 adverse events were neutropenia (28%) and elevation in AST (10%). Dose limiting toxicities were reversible elevations in transaminase and bilirubin, neutropenia or febrile neutropenia and pneumonia.

Abstract: 2503
Title: Phase I study of sapacitabine and seliciclib in patients with advanced solid tumors
Date/Time: June 6, 2016 9:00 a.m. — 9:12 a.m. CDT
Location: E354b
Session Title: Developmental Therapeutics—Clinical Pharmacology and Experimental Therapeutics
Authors: SM Tolaney1, J Hilton1, JM Cleary1, L Gandhi1, EL Kwak1, JW Clark1, A Wolanski1, T Bell1, SJ Rodig3, JH Chiao2, D Blake2, G Shapiro1
1Dana-Farber Cancer Institute, Boston, MA; Massachusetts General Hospital Cancer Center, Boston, MA; 2 Cyclacel Ltd, Dundee, United Kingdom; 3 Brigham and Women’s Hospital, Boston, MA.

The abstract can be accessed through the ASCO (Free ASCO Whitepaper) website, View Source

About sapacitabine

Sapacitabine is an oral nucleoside analogue prodrug whose metabolite, CNDAC, generates single-strand DNA breaks (SSB), either leading to arrest of the cell cycle at G2 phase or development of double-strand DNA breaks (DSB). CNDAC-induced DSB repair is dependent on homologous recombination (HR). BRCA mutations in cancer cells are a cause of HR deficiency, making them susceptible to cell death induced by sapacitabine. Sapacitabine is the subject of SEAMLESS, a Phase 3 trial, which has completed enrollment and is being conducted under an SPA with the U.S. Food and Drug Administration (FDA) as front-line treatment for acute myeloid leukemia (AML) in the elderly. Sapacitabine has been evaluated to date in over 1000 patients including randomized Phase 2 and 3 trials in patients with hematological malignancies and previously treated solid tumors, including lung cancer.

About seliciclib

Seliciclib is an orally-available CDK inhibitor molecule that selectively inhibits enzyme targets, CDK2 and CDK9, which are central to the process of cell growth, survival and cell cycle control. Seliciclib treatment has been reported to inhibit the two major DNA double-strand break (DSB) repair pathways, homologous recombination (HR) and non-homologous end joining (NHEJ), by reducing expression of components of each pathway. It may potentiate the activity of sapacitabine by compromising HR protein expression and activation or by potentiating apoptosis following sapacitabine-induced DNA damage. Seliciclib has been evaluated to date in approximately 450 patients including randomized Phase 2 trials in patients with previously treated lung cancer and nasopharyngeal cancer.