Mundipharma Announces Next Milestone For Tinostamustine (EDO-S101) As First-In-Human Solid Tumor Study Begins

The initial phase of the new study has been designed to determine the safety, tolerability, maximum dose and optimal dosing schedule of tinostamustine as a single agent in patients with solid tumors, who have progressed after at least one line of therapy and no other standard therapy with proven clinical benefit is available. It will also investigate the pharmacokinetic profile. The study will then expand to evaluate toxicity and response rates in selected relapsed/refractory solid tumors including: small cell lung cancer (SCLC); soft tissue sarcoma (STS) or non-KIT gastrointestinal stromal tumors (GIST); triple negative breast cancer (TNBC); and ovarian cancer.

Although an effective option for some cancer patients, traditional DNA-damaging therapies have certain limitations which can result in resistance, for example, a failure to gain access to the DNA strands to break them or an inability to counteract the DNA repair mechanisms within cancer cells.^[1]

Tinostamustine (EDO-S101) is an AK-DACi (a first-in-class alkylating deacetylase inhibiting molecule) that, in preclinical studies, has been shown to improve access to the DNA strands within cancer cells, break them and counteract damage repair.^[2]-[4] Preclinical studies suggest that these complementary and simultaneous modes of action have the potential to overcome resistance.^[4],[5]

Preclinical experiments in solid tumors show that tinostamustine exhibits efficacy in most SCLC cell lines, including those that are resistant to doxorubicin.^[5],[6] Activity has also been established in
preclinical studies for STS, TNBC and ovarian cancer.^[6]

Dr. Thomas Mehrling, CEO of EDO commented: “Following the initial Phase 1 study in hematological malignancies, I am delighted that EDO is now embarking on a further clinical trial in solid tumors. People with advanced solid tumors can become resistant to treatment and often have a relatively poor chance of survival. Breaking through resistance is essential if we are to continue to address
unmet needs in oncology. This is a key step in the investigation of a first-in-class treatment, which we hope will prove a vital addition for patients with limited current options.”

About EDO
EDO is focused on the preclinical and clinical development of treatments for cancer types where there are currently limited options for patients. EDO supports the rapid development of innovative new treatments from initial concept right through to the late stages of clinical development.

EDO is part of the Mundipharma global network of privately-owned independent associated companies, which operate in over 120 countries worldwide.

For further information, please visit http://www.edoncology.com

About the study
The primary objective of the Phase 1/2 multicenter, clinical trial is to assess the safety, tolerability, maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of tinostamustine as a single agent in patients with solid tumors who have progressed after at least one line of therapy and no other standard therapy with proven clinical benefit is available. MTD will be established for two administration schedules. The secondary objective will be to establish the pharmacokinetic (PK) profile of tinostamustine. There will be an exploratory objective to correlate the extent of gene expression changes in tumor samples with anti-tumor activity. The study will take place at Stanford University, Cedars Sinai Medical Center (Los Angeles) and The Mayo Clinic (Scottsdale).

In the second phase, the study will expand into selected solid tumor cohorts including: relapsed SCLC; relapsed STS or non-KIT GIST; relapsed/refractory TNBC; and relapsed/refractory ovarian cancer. The primary objective of Phase 2 will be to assess objective response rate (ORR) and clinical benefit rate (CBR). The secondary objectives will include safety, progression-free survival, overall survival, duration of response and PK profiles.

For further information about the study please visit: http://www.clinicaltrials.gov

About Solid Tumours
Patients with advanced stage SCLC have a low chance of survival (8% relative 5-year survival rate for Stage III and 2% for Stage IV).^[7]

Approximately 16% of patients with STS have advanced stage (metastatic) disease. For these patients, the relative 5-year survival rate is 16%.^[8]

TNBC tends to be more aggressive than other types of breast cancer, is more likely to spread beyond the breast and more likely to recur after treatment. Relative 5-year survival rates are lower for TNBC than for other types of breast cancer. TNBC is not a good candidate for hormonal therapy or HER2 targeting treatments.^[9]

Ovarian cancer is the seventh most common cause of cancer-related deaths in women worldwide.^[10] Relative 5-year survival rates vary significantly depending on cancer stage. The outlook is worse for those with advanced ovarian cancer.^[11]

References

1. Cheung-Ong K, et al. DNA-Damaging Agents in Cancer Chemotherapy: Serendipity and Chemical Biology. Chemistry & Biology 2013;20:648-59.
2. Lo´pez-Iglesias AA. The Alkylating Histone Deacetylase Inhibitor Fusion Molecule Edo-S101 Displays Full Bi-Functional Properties in Preclinical Models of Hematological Malignancies. Blood 2014; 124: (21). https://ash.confex.com/ash/2014/webprogram/Paper72121.html
3. Lo´pez-Iglesias AA. preclinical antimyeloma activity of EDO-S101 (bendamustine-vorinostat fusion molecule) through DNA-damaging and HDACi effects. 15^th International Myeloma Workshop. 23-26 September 2015. Rome, Italy.
4. Di Filippi R, et al. The First-In-Class Alkylating Histone Deacetylase Inhibitor (HDACi) Fusion Molecule EDO-S101 Exerts Potent Preclinical Activity Against Tumor Cells of Hodgkin Lymphoma (HL) Including Bendamustine Resistant Clones. 57^th Annual Meeting and Exposition of the American Society of Hematology (ASH), 6 December 2015.
5. Yan S, Xu K, Lin J, et al. Synergistic inhibition of tumor growth and overcoming chemo-resistance by simultaneously targeting key components in DNA damage/repair, epigenetic, and putative cancer stem cell signaling pathways using novel dual-functional DNA-alkylating/HDAC inhibitor and tumor suppressor gene nanoparticles in lung cancer. Cancer Research 2012;72( Suppl 1): Abstract 2741.
6. Mundipharma EDO GmbH Data on file.

https://ash.confex.com/ash/2014/webprogram/Paper70113.html

1. National Cancer Institute SEER Database (1988-2001). American Cancer Society website. Last accessed April 2017: https://www.cancer.org/cancer/small-cell-lung-cancer/detection-diagnosis-staging/survival-rates.html
2. National Cancer Institute. American Cancer Society website: Last accessed April 2017: https://www.cancer.org/cancer/soft-tissue-sarcoma/detection-diagnosis-staging/survival-rates.html
3. Breastcancer.org website. Last accessed April 2017: http://www.breastcancer.org/symptoms/diagnosis/trip_neg/behavior
4. Jemal A, et al. Global Cancer Statistics. Ca Cancer J Clin 2011;61:69-90.
5. National Cancer Institute SEER database (2004-2010). American Cancer Society website. Last accessed April 2017: https://www.cancer.org/cancer/ovarian-cancer/detection-diagnosis-staging/survival-rates.html

SOURCE Mundipharma EDO GmbH (EDO)