A Study of DSP-0509 in Patients With Advanced Solid Tumors to Determine the Safety and the Pharmacokinetic Profile

This is a multi-center, Phase 1 / 2 clinical study for patients with advanced solid tumors. The study consists of 2 treatment arms - a monotherapy arm and a combination arm. The monotherapy arm has 1 part: Dose Escalation (Part A). The combination arm has Dose Escalation (Part B) only.

The primary objective of Monotherapy Arm A is to determine the MTD or RP2D of DSP-0509 when administered as a single agent. Approximately 21 to 30 patients with advanced solid tumors will be enrolled. Several provisional dose levels of DSP-0509, with approximately 3 to 6 patients at each level may be tested in patients with advanced solid tumors. DSP-0509 will be administered as a single agent q2w beginning on Day 1.

The primary objective of Combination Therapy Arm B is to determine the RP2D of DSP-0509 when administered in combination with pembrolizumab, using a BLRM approach. The combination arm will enroll approximately 21 to 30 patients with advanced solid tumors that are (a) metastatic or unresectable and recurrent, and/or refractory to available therapy, (b) a condition for which pembrolizumab is an approved treatment, and (c) in patients who have shown either primary or acquired resistance to an ICI. DSP-0509 will be administered on Day 1 and then every 2 weeks thereafter. Pembrolizumab will be initiated on Day 1.

The primary objective of Combination Therapy Arm C is to determine preliminary efficacy in the form of the ORR of DSP-0509 when administered in combination with pembrolizumab to an expansion cohort of patients with HNSCC, using a Bayesian Adaptive design approach. Combination Arm C will enroll approximately 20 to 40 patients with HNSCC tumors that are (a) metastatic or unresectable, and recurrent and/or refractory to available therapy, (b) in patients who have been treated with pembrolizumab or other PD-1 or PD-L1 inhibitors in monotherapy, and (c) who have subsequently shown either primary or acquired resistance to ICIs.

Dose escalation of DSP-0509 in combination with 400 mg pembrolizumab q6w will start at the same dose of DSP-0509 as the highest (not exceeding the MTD) level tested in the combination regimen with 200 mg pembrolizumab q3w. Upon completion of the DLT evaluation period for the first DSP-0509 dose level tested in combination with 400 mg pembrolizumab q6w in newly enrolled patients, if this dose level is found not to exceed the MTD, any ongoing patients receiving DSP-0509 in combination with pembrolizumab 200 mg q3w will be allowed, at the investigator's discretion, to transition to the 400 mg pembrolizumab q6w regimen, while maintaining the originally assigned DSP-0509 dose level.

Eligibility Criteria:
Inclusion Criteria:

Patients must fulfill each of the following requirements:

1. Must have a histologically or cytologically confirmed advanced solid tumor that meets the following additional specifications

1. Monotherapy Part A (Dose Escalation) advanced solid tumor that is metastatic or unresectable and recurrent and /or refractory to available therapy.
2. Combination Part B (Dose Escalation)- advanced solid tumors that are (a) metastatic or unresectable and recurrent and/or refractory to available therapy; (b) a condition for which pembrolizumab is an approved treatment: and (c) in patients who either have shown primary or acquired resistance to immune checkpoint inhibitors (ICIs)
3. Combination Arm C (Dose Expansion), Phase 2 - Advanced HNSCC tumors of the oropharynx, oral cavity, hypopharynx, larynx, lip, or sinus that are (a) metastatic or unresectable, and recurrent and/or refractory to available therapy, (b) in patients who have been treated with pembrolizumab or other PD-1 or PD-L1 inhibitors in monotherapy, and (c) who have subsequently shown primary or acquired resistance to ICIs.

   For enrollment in both arms:

   2. Must be ≥ 18 years of age

   3. Should have all side effects of any prior therapy or procedures for any medical condition recovered to CTCAE ≤ Grade 1 (except alopecia).

   4. Must have at least 1 measurable lesion by computed tomography or magnetic resonance imaging per RECIST v1.1.

   5. Must have a life expectancy ≥ 3 to 6 months.

   6. Female patients of childbearing age and women \< 12 months since the onset of menopause, except those who have been surgically sterilized (tubal ligation) or whose sexual partner(s) is surgically sterilized (vasectomy), must agree to use acceptable contraceptive methods for the duration of the study and for 9 months after the date of their last DSP-0509 infusion. If employing contraception, 2 of the following precautions must be used: birth control pill, vaginal diaphragm, intrauterine system or device, condom or vaginal spermicide. Female patients who are postmenopausal are defined as those with an absence of menses for ≥ 12 consecutive months. Male patients must be surgically sterilized (vasectomy) or their female sexual partner(s) must be surgically sterilized (tubal ligation) to avoid using contraception. If they do not meet this criterion, then male patients or must agree to use a condom as well as one of the acceptable contraceptive methods listed above with their female partner(s) who meets the criteria of either being of childbearing age or is \< 12 months since the onset of menopause. Male patients and their female partner(s) must agree to use acceptable contraception methods for the duration of time the male patient is on the study and for 9 months after the date of his last DSP 0509 infusion.

   7. Females of childbearing potential must have a negative serum pregnancy test.

   8. Must have an Eastern Cooperative Oncology Group performance status of 0 to 1.

   9. Must have adequate coagulation function at Screening as determined by:

a. Prothrombin international normalized ratio \< 1.5. b. Partial thromboplastin time \< 1.5 times the upper limit of normal (ULN).

10. Must have adequate hematologic function at Screening as determined by:

a. White blood cell (WBC) count ≥ 3,000/microliter. b. Absolute neutrophil count (ANC) ≥ 1,500/microliter (patient may not use granulocyte colony stimulating factor or granulocyte-macrophage colony stimulating factor to achieve these WBC and ANC levels).

c. Platelet count ≥ 100 × 103/microliter. d. Hemoglobin (Hgb) ≥ 9.0 g/dL (may not transfuse or use erythropoietin to obtain this Hgb level).

11. Must have adequate renal and hepatic function at Screening as determined by:

1. Serum creatinine \< 2.0 mg/dL or \< 1.5 times the ULN, whichever is lower.
2. Total bilirubin ≤ 1.5 mg/dL or \< 1.5 times the ULN, whichever is lower (or ≤ 2.0 mg/dL for patients with known Gilbert syndrome).
3. Aspartate aminotransferase ≤ 2.5 times ULN (≤ 5 times ULN for patients with liver metastases).
4. Alanine aminotransferase ≤ 2.5 times ULN (≤ 5 times ULN for patients with liver metastases).

   12. Must be able to attend study visits as required by the protocol.

   13. Prior to the first DSP-0509 infusion, the patient must be able to provide tumor tissue for baseline studies either as (a) a block of archival tissue sufficient to provide the required number of slides (b) a sufficient number of fixed, unstained slides of archival tissue or (c) consent to undergo tumor biopsy to acquire sufficient tumor tissue. (Sites need to refer to the current version of the "Sample Collection \& Shipment Instructions Manual" to determine how many slides are required for each patient as these numbers vary based on (a) the study Arm/Part in which the patient is enrolled and (b) whether the patient consented to optional future testing).

   In addition to the above criteria, patients must meet the following criteria to be eligible to enroll in Combination Arm C:

   14. Have at least one accessible tumor for biopsy. This accessible lesion must be considered as non-measurable per RECIST criteria, v1.1.

   15. Be platinum refractory, PD-1 or PD-L1 exposed, and have no more than 3 lines of prior therapy for advanced/metastatic disease

   16. Have a known status of PD-L1 combined positive score (CPS)

   17. Have a known HPV status

   Exclusion Criteria:

   Patients with any of the following will be excluded from the study:

   For enrollment in both arms:
   1. Has received prior therapy with a TLR agonist, excluding a topical TLR agonist.
   2. Has received anticancer chemotherapy (including molecular-targeted drugs), radiotherapy, immunotherapy (eg, vaccines or cytokines), or investigational agents within the 3 weeks before the first dose of DSP-0509. Local palliative radiotherapy is permitted3. Receives concurrent systemic (oral or IV) steroid therapy \> 10 mg prednisone daily or its equivalent for an underlying condition.

   4. Not fully recovered from major surgery before the first dose of DSP-0509.

   5. Has central nervous system (CNS) metastases (including leptomeningeal metastases, spinal metastases) or CNS primary tumors, eg, glioblastoma.

   6. Has a history of seizures other than isolated febrile seizure in childhood; has a history of a cerebrovascular accident or transient ischemic attack less than 6 months ago.

   7. Has effusions (pleural, pericardial, or ascites) requiring drainage.

   8. Has a neurodegenerative disease, eg, motor neuron disease, Parkinson disease, Alzheimer disease, Huntington disease.

   9. Has retinal detachment, ulcerative keratitis, uveitis, Vogt-Koyanagi-Harada syndrome, choroidal neovascularization, retinopathy/retinitis, thyroid-associated orbitopathy, idiopathic orbital inflammation, diabetic retinopathy, ischemic retinopathy including glaucoma-associated retinopathy, retinal vein thrombosis, or a non-healing ocular or ophthalmic disease.

   10. Has a fever ≥ 38°C within 3 days before the first dose of study treatment.

   11. Has interstitial lung disease or active noninfectious pneumonitis.

   12. Has a history of active autoimmune or immunologic disorder requiring immunosuppression with steroids or other immunosuppressive agents (eg, azathioprine, cyclosporine A) except for patients with isolated vitiligo, resolved childhood asthma or atopic dermatitis, controlled hypoadrenalism or hypopituitarism, and euthyroid patients with a history of Grave disease. Patients with controlled hyperthyroidism must be negative for thyroglobulin, thyroid peroxidase antibodies, and thyroid-stimulating immunoglobulin before study drug administration.

   13. Has a known hypersensitivity to a component of the protocol therapy, DSP-0509, or another pyrimidine.

   14. Has a history of another primary cancer within the 5 years before enrollment except for the following: non-melanoma skin cancer, cervical carcinoma in situ, superficial bladder cancer, or other nonmetastatic carcinoma that has been in complete remission without treatment for more than 5 years.

   15. Has abnormal ECGs that are clinically significant, such as QT prolongation (QTc \> 480 msec).

   16. In the opinion of the treating Investigator, has any concurrent conditions that could pose an undue medical hazard or interfere with the interpretation of the study results; these conditions include, but are not limited to ongoing or active infection, clinically significant non-healing or healing wounds, concurrent congestive heart failure (New York Heart Association Functional Classification Class II, III or IV), concurrent unstable angina, concurrent cardiac arrhythmia requiring treatment (excluding asymptomatic atrial fibrillation), recent (within the prior 12 months) myocardial infarction, acute coronary syndrome within the previous 12 months, significant pulmonary disease (shortness of breath at rest or on mild exertion) for example due concurrent severe obstructive pulmonary disease, concurrent hypertension requiring more than 2 medications for adequate control, or diabetes mellitus with more than 2 episodes of ketoacidosis in the prior 12 months.

   17. Has an ejection fraction of 50% or less based on a MUGA scan or ECHO.

   18. Has the presence of a known active acute or chronic infection including human immunodeficiency virus as determined by enzyme-linked immunosorbent assay and confirmed by Western blot; and hepatitis B virus and hepatitis C virus as determined by hepatitis B surface antigen and hepatitis C serology.

   19. Has a cognitive, psychological, or psychosocial impediment that would impair the ability of the patient to receive therapy according to the protocol or adversely affect the ability of the patient to comply with the informed consent process, protocol, or protocol-required visits and procedures.

   20. Receives concurrent strong inhibitors of cytochrome P450 2C8.

   21. Receives concurrent inhibitors of organic anion transporting peptide (OATP)1B1 and OATP1B3.

   22. Is pregnant or breastfeeding.

   23. Has active neurological or inflammatory or auto immune disorders (e.g. Guillain-Barre Syndrome, Amyotrophic Lateral Sclerosis)

   The following exclusion applies only to enrollment in Combination arms Part B \& C:

   24. Has a history of immune-related adverse events (irAEs) resulting in permanent discontinuation of ICI treatment.