Study of the Safety, Pharmacokinetics and Efficacy of Tinostamustine in Patients With Advanced Solid Tumors.

Tinostamustine (EDO-S101) is a first-in-class alkylating deacetylase inhibitor designed to improve drug access to deoxyribonucleic acid (DNA) strands, induce DNA damage and counteract its repair in cancer cells. The main purpose of this study is to assess the safety, tolerability and efficacy of Tinostamustine in subjects with advanced solid tumours. Subjects will be given Tinostamustine via intravenous infusion on Days 1 and 15 of a 4-week cycle, the dose and infusion time will vary depending on the phase of the study.

The study consists of 2 phases and 2 sub-studies:

This study is a multi-centre, open-label phase 1/2 study of single agent EDO-S101 in subjects with advanced solid tumours.

Phase 1 part of the study is designed to determine the safety, tolerability, maximum tolerated dose (MTD), recommended phase 2 dose (RP2D) and the Pharmacokinetic (PK) of EDO-S101 as a single agent in patients with solid tumours who have progressed after at least one (1) line of therapy and for whom no other standard therapy with proven clinical benefit is available.

Phase 2 part of the study is designed to evaluate the overall response rate (ORR) of the RP2D, plus the rate of patients with stable disease (SD) at 4 or 6 months, depending on the type of solid tumour. The RP2D was determined after phase 1 to be 80 mg/m2 of EDO-S101 administered over 1 hour on Day 1 and Day 15 of each 4-week treatment cycle.

In addition, two sub-studies are designed to better characterize the effect of EDO-S101: one at a dose of 60 mg/m2 administered over 60 minutes and the second at a dose of 80 mg/m2 administered over 80 minutes on cardiac repolarization (QTc) and other ECG parameters in the subjects with solid tumours.

Subjects were eligible for these studies if they had a histologically confirmed solid tumour, signed informed consent and met the inclusion/exclusion criteria. After providing informed consent, subjects were screened, and all procedures were performed as per protocol.

Eligibility Criteria:
Inclusion and exclusion criteria were reviewed for each potential patient during Screening. All eligible patients were treated with Tinostamustine employing sequential enrollment (i.e. as they qualify for participation). In the first phase of the trial (Phase 1), the dose received for each eligible patient was dependent on the requirements of the dose escalation scheme at the time the patient was enrolled. In the second phase of the trial (Phase 2), all patients were treated with the Tinostamustine at 80 mg/m2 administered over 1 hour on Day 1 and 15 of each 4-week treatment cycle.

General Inclusion Criteria for Phase 1 and Phase 2 portions of Study:

1. Patient willing and able to sign the informed consent.
2. Patients age ≥18 years at signing the informed consent.
3. Life expectancy \> 3 months.
4. Histologically confirmed diagnosis of advanced or metastatic solid tumors, disease should have progressed following at least one line of therapy and no other standard therapy with proven clinical benefit is available or recommended based on the investigator's individual risk-benefit assessment for the patient.
5. Patients with secondary metastasis to the central nervous system (CNS) are eligible if they have had brain metastases resected or have received radiation therapy ending at least 4 weeks prior to trial day 1 and they meet all of the following criteria:

   1. Residual neurological symptoms ≤Grade 1.
   2. No glucocorticoids requirement or patients may be receiving low doses of glucocorticoids providing the dose has been stable for at least 2 weeks prior to starting the trial medication.
   3. Follow-up imaging studies show no progression of treated lesions and no new lesions.
6. Evaluable disease; measurable on imaging as assessed by RECIST version 1.1.
7. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
8. Absolute neutrophil count (ANC) (polymorphonuclear cells \[PMN\] plus bands) \>1,000/ μL.
9. Platelets ≥100,000 μL. Platelet transfusions within the 14 days before Day 1 of Cycle 1 is prohibited.
10. Aspartate aminotransferase/alanine aminotransferase (AST/ALT) ≤ 3 upper limit of normal (ULN). In cases with liver involvement ALT/ AST ≤ 5× ULN.
11. Total bilirubin ≤1.5 mg/dL unless elevated due to known Gilbert's syndrome.
12. Creatinine ≤1.5 ULN.
13. Serum potassium and magnesium at least at the lowest limit of normal (LLN), before every IMP administration. If it is below the LLN, supplementation is permissible.
14. Female study participants of child-bearing potential and their partners, and male study participants who intend to be sexually active with a woman of child-bearing potential, must be willing to use at least two (2) highly effective forms of contraception. This should start from the time of study enrollment and continue throughout IMP administration. For female study participants of child-bearing potential this must continue using contraception for at least six (6) months after the last administration of the IMP. Female study participants should be willing to have a pregnancy test performed at screening, ≤ 1 day prior to day 1 of each IMP administration and at study treatment discontinuation. Male study participants who are sexually active with a woman of child-bearing potential should also use a condom during treatment and for at least ninety (90) days after the last administration of IMP. Vasectomized males are considered fertile; therefore, vasectomized partners and patients must be willing to use a secondary method of effective birth control. Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the trial treatment. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient.

Exclusion Criteria Phase 1 and Phase 2 portions of Study:

To be eligible to participate in the trial, a patient cannot meet any of the following exclusion criteria:

1. Patients with primary central nervous system (CNS) cancer.
2. Patients with QTc interval (Fridericia's formula) \>450 msec.
3. Patients who are on treatment with drugs known to prolong the QT/QTc interval.
4. Patients who are being treated with Valproic Acid for any of its indication (epilepsy, mood disorder).
5. Any serious medical condition that interferes with adherence to trial procedures.
6. Prior history of solid tumor malignancy diagnosed within the last three (3) years of study enrollment excluding adequately treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer, in situ breast cancer, in situ prostate cancer (patients must have shown no evidence of active disease for 2 years prior to enrollment)
7. Pregnant or breast feeding females.
8. New York Heart Association (NYHA) stage III/IV congestive heart failure, arrhythmias not adequately controlled, or other significant co-morbidities \[e.g. active infection requiring systemic therapy, history of human immunodeficiency virus (HIV) infection, or active Hepatitis B or Hepatitis C\].
9. Use of other investigational agents within 28 days prior to the first dose of study drug, provided the patient has recovered from any related toxicities ≥Grade 1.
10. Steroid treatment within seven (7) days prior to trial treatment. Patients that require intermittent use of bronchodilators, topical steroids or local steroid injections will not be excluded from the study. Patients who have been stabilized to 10 mg Prednisolone orally (PO) once daily (QD) (or equivalent), daily (or less) at least seven (7) days prior to IMP administration are allowed.

Phase 2:

Patients must meet the cohort-specific inclusion/exclusion criteria in addition to the general inclusion/exclusion criteria for Phase 1 and Phase 2 study listed above.

Cohort 1: Relapsed/Refractory small cell lung cancer (SCLC)

1. Histologically or cytologically confirmed limited or extensive disease stage of SCLC.
2. Must have received at least 1 line of prior combination chemotherapy or biological therapy and no other standard therapy with proven clinical benefit is available or recommended based on the investigator's individual risk-benefit assessment for the patient.
3. At least 28 days should have elapsed since prior treatment as long as the patient has recovered from any related toxicities to ≤ Grade 1 (or ≤ Grade 2 for any symptomatic neuropathy or endocrinopathies).
4. Prior radiotherapy is acceptable provided the patient has recovered from any radiotherapy related acute toxicities.
5. The disease should be progressing during or relapsing after the previous treatment.
6. Presence of measurable disease as defined by RECIST version 1.1. Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-regional therapy, are usually not considered measurable unless there has been demonstrated progression in the lesion.

Cohort 2: Relapsed/Refractory Soft Tissue Sarcoma (STS)

1. Histologically confirmed diagnosis of advanced, unresectable, or metastatic soft tissue sarcoma not amenable to curative treatment with surgery or radiotherapy excluding: neuroblastoma, GIST, embryonal rhabdomyosarcoma, Kaposi sarcoma, chondrosarcoma, osteosarcoma or Ewing's sarcoma.
2. Must have received at least one prior line prior line chemotherapy or biological therapy regimen and no other standard therapy with proven clinical benefit is available or recommended based on the investigator's individual risk-benefit assessment for the patient. At least twenty-eight (28) days should have elapsed since prior chemotherapy, as long as the patient recovered from any related toxicities to ≤ Grade 1 (or ≤Grade 2 for any symptomatic neuropathy or endocrinopathies).
3. The disease should be progressing during or relapsing after the previous treatment.
4. Presence of measurable disease as defined by RECIST version 1.1. Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-regional therapy, are usually not considered measurable unless there has been demonstrated progression in the lesion.

Cohort 3: Relapsed/Refractory Triple Negative Breast Cancer (TNBC)

1. Histologically or cytologically confirmed locally advanced or metastatic Triple Negative Breast Cancer. Proven human epidermal growth factor receptor 2 (HER2) negative by immunohistochemistry (INH) or in situ hybridization (ISH) per per American Society of Clinical Oncology - College of American Pathologists (ASCO-CAP) guidelines.
2. Must have received at least one (1) line of chemotherapy or biological therapy and no other standard therapy with proven clinical benefit was available or recommended based on the Investigator's individual risk-benefit assessment for the subject.
3. At least three (3) weeks should have elapsed since prior chemotherapy as long as the subject recovered from acute toxicity of previous therapies to ≤ Grade 1 (or ≤ Grade 2 for any symptomatic neuropathy or endocrinopathies).
4. Prior radiotherapy was acceptable provided it was administered at least four (4) weeks (two (2) weeks for palliative, limited field radiation therapy) prior to starting treatment on this study and the subject recovered from any radiotherapy related acute toxicities.
5. The disease had to be progressing during or relapsing after the previous treatment.
6. Presence of measurable disease as defined by RECIST version 1.1. Tumour lesions situated in a previously irradiated area, or in an area subjected to other loco-regional therapy, were usually not considered measurable unless there had been demonstrated progression in the lesion.

Cohort 4: Patient Population: Relapsed/Refractory Ovarian Cancer (OC)

1. Histologically or cytologically confirmed advanced ovarian cancer: epithelial ovarian cancer, including primary peritoneal cancer or fallopian tube cancer (excluding borderline ovarian cancer, MMMT) of high grade serous histology, or high grade endometrioid cancer, that is resistant or refractory to platinum therapy and no other standard therapy with proven clinical benefit is available or recommended based on the investigator's individual risk-benefit assessment for the patient. Clear cell carcinomas are excluded. Patients with primary platinum refractory disease (failure to respond to initial platinum treatment or relapse within four (4) weeks) and patients with primary platinum resistant disease (progression within six (6) months of completing first line platinum-based therapy) are excluded from the study.
2. At least twenty eight (28) days should have elapsed since prior chemotherapy as long as the patient recovered from acute toxicity of previous therapies to ≤ Grade 1 (or ≤ Grade 2 for any symptomatic neuropathy or endocrinopathies).
3. The disease should be progressing during or relapsing after the previous treatment.
4. Presence of measurable disease as defined by RECIST version 1.1. Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-regional therapy, are usually not considered measurable unless there has been demonstrated progression in the lesion.

Cohort 5: Relapsed/Refractory Endometrial Cancer (EC)

1. Histologically or cytologically confirmed locally advanced or metastatic endometrial cancer (excluding leiomyosarcoma and carcinosarcoma)
2. Must have received at least one (1) line of chemotherapy and no other standard therapy with proven clinical benefit is available or recommended based on the investigator's individual risk-benefit assessment for the patient. At least three (3) weeks should have elapsed since prior chemotherapy or 5 half-lives, whichever is shorter, as long as the patient recovered from acute toxicity of previous therapies to ≤ Grade 1 (or ≤ Grade 2 for any symptomatic neuropathy or endocrinopathies).
3. Prior radiotherapy is acceptable provided it was administered at least four(4) weeks (two (2) weeks for palliative, limited field radiation therapy) prior to starting treatment on this trial and recovered from any radiotherapy related acute toxicities.
4. The disease should be progressing/relapsed during or after the previous treatment.
5. Presence of measurable disease as defined by RECIST version 1.1. Tumour lesions situated in a previously irradiated area, or in an area subjected to other loco-regional therapy, were usually not considered measurable unless there had been demonstrated progression in the lesion.