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 Part A in the monotherapy arm is to determine the RP2D of DSP-0509
when administered as a single agent. Approximately 21 to 30 patients with advanced solid
tumors will be enrolled. At the time of this amendment, 12 patients have been enrolled in the
monotherapy cohorts with dose levels of 0.3, 1, and 1.5 mg DSP-0509 given once per week and
completed the DLT period. Based on review of DLTs and consistent with the BLRM model, the
Safety Review Committee has assessed that continuing at the 1.5 mg dose level is appropriate.
Under Protocol Amendment 4, the dose level of 1.5 mg given every two weeks will be applied in
Monotherapy Part A. Enrollment of additional cohorts will be based on the dose escalation
The primary objective of Combination Part B is to determine the RP2D of DSP-0509 when
administered in combination with pembrolizumab, using a BLRM approach as described above. 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) the patients have shown
either primary or acquired resistance to an ICI. Under protocol amendment 4, DSP-0509 will be
administered on Day 1 and then every 2 weeks thereafter. Pembrolizumab will be initiated on
Day 8 and administered using the dose and schedule described (200 mg IV every 3 weeks).
To maximize patient safety, enrollment in the first combination escalation cohort will begin
at dose level of 0.3 mg DSP-0509 after safety and tolerability of DSP-0509 monotherapy has
been confirmed at least 1 dose level higher.
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
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.
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:
1. Prothrombin international normalized ratio < 1.5.
2. Partial thromboplastin time < 1.5 times the upper limit of normal (ULN).
10. Must have adequate hematologic function at Screening as determined by:
1. White blood cell (WBC) count ≥ 3,000/microliter.
2. 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).
3. Platelet count ≥ 100 × 103/microliter.
4. 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
4. Alanine aminotransferase ≤ 2.5 times ULN (≤ 5 times ULN for patients with liver
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
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,
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
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
13. Has a known hypersensitivity to a component of the protocol therapy, DSP-0509, or
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
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.