Clinical Trials /

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

NCT03416335

Description:

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.

Related Conditions:
  • Cervical Carcinoma
  • Gastric Carcinoma
  • Head and Neck Squamous Cell Carcinoma
  • Hepatocellular Carcinoma
  • Malignant Solid Tumor
  • Melanoma
  • Merkel Cell Carcinoma
  • Non-Small Cell Lung Carcinoma
  • Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study of DSP-0509 in Patients With Advanced Solid Tumors to Determine the Safety and the Pharmacokinetic Profile
  • Official Title: A First-in-Human Phase 1/2 Trial to Determine the Safety and the Pharmacokinetic Profile of DSP-0509, a Synthetic Toll-Like Receptor 7 (TLR-7) Agonist, Administered as Monotherapy and in Combination With Pembrolizumab in Adult Patients With Advanced Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: BBI-DSP0509-101
  • NCT ID: NCT03416335

Conditions

  • Neoplasms

Interventions

DrugSynonymsArms
DSP-0509Monotherapy Arm - Part A
DSP-0509, PembrolizumabCombination arm - Part A

Purpose

This is a multi-center, Phase ½ 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 3 parts: Dose Escalation (Part A), Dose Expansion (Part B) and Maintenance Dose Schedule Evaluation (Part C). The combination arm has Dose Escalation (Part A) only.

Detailed Description

      The study consists of two treatment arms- a monotherapy arm and a combination arm. The
      monotherapy arm has 3 parts: the Dose Escalation part (Part A) will evaluates 5 provisional
      dose levels/cohorts (3-6 patients in each cohort) and will enroll approximately 21-30
      patients with solid tumors based on the Bayesian Logistic Regression Model (BLRM) method with
      the Escalation with Overdose Control (EWOC) principle to determine the maximum tolerated dose
      (MTD). DSP-0509 will be administered as a single agent q1w for 4 weeks beginning on Day 1
      during induction treatment followed by q2w administration until discontinuation during
      maintenance treatment. Within each cohort, patients will be entered in a staggered fashion as
      an additional safety measure. That is, treatment of a new patient will be delayed at least 48
      hours after the first dose of the most recent patient entered within each cohort.

      Next is the Dose Expansion part (Part B) in which approximately 20-40 total patients with a
      diagnosis of either melanoma or head and neck squamous cell carcinoma (HNSCC) will be broken
      out into each of the following 4 sub-groups (5 to 10 patients per group): Melanoma CD8+ high,
      melanoma CD8+ low, HNSCC CD8+ high and HNSCC CD8+ low. These patients will be treated using
      the RP2D of DSP-0509 which is given to them intravenously once a week in induction phase, and
      once every two weeks in a maintenance phase. If clinical benefit is seen, treatment can
      continue until disease progression.

      The 3rd part of monotherapy is the Maintenance Dose Schedule Evaluation (Part C) which will
      enroll approximately 3-6 patients with solid tumors to assess the safety and tolerability of
      DSP-0509 using the RP2D that will be administered IV once a week (q1w) during the induction
      treatment followed by every 3 weeks (q3w) during maintenance treatment to these patients.

      The second treatment arm, combination arm, has just 1 part. The Dose Escalation part (Part A)
      will start once safety and tolerability has been confirmed for the 2nd dose escalation cohort
      in monotherapy Part A. The starting dose level of DSP-0509 will be at least 1 dose level
      below that of the second dose level tolerated in monotherapy Part A. Approximately 21-30
      patients with solid tumors will be enrolled into Part A of the combination arm. DSP-0509 will
      be administered using the same dosing schedule as monotherapy arm Part A. Pembrolizumab will
      be administered using a dose and schedule as described in the approved label (200 mg IV q3w).
      Within each cohort, patients will be entered in a staggered fashion (48 hrs. between the dose
      another patient) as an additional safety measure.
    

Trial Arms

NameTypeDescriptionInterventions
Monotherapy Arm - Part AExperimentalDose Escalation
  • DSP-0509
Monotherapy arm - Part BExperimentalDose Expansion
  • DSP-0509
Monotherapy arm - Part CExperimentalMaintenance Dose Schedule Evaluation
  • DSP-0509
Combination arm - Part AExperimentalDose Escalation
  • DSP-0509, Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

        Patients must fulfill each of the following requirements:

        For enrollment in monotherapy arm only:

          1. Must have a histologically or cytologically confirmed

               1. Part A & C advanced solid tumor that is metastatic or unresectable and recurrent
                  and/or refractory to available therapy.

               2. Part B - metastatic or unresectable and recurrent

                    -  Melanoma with acquired resistance to ICIs (defined as previous treatment
                       with ICIs [PD 1 or PD-L1 inhibitors] accompanied by objective clinical
                       benefit [SD for at least 24 weeks, PR, or CR as the best clinical response
                       to ICIs], followed by systemic progression of disease during or within 3
                       months after the last dose of ICI treatment according to Investigator
                       judgement).

                    -  HNSCC with 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 or urine 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
                  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. For monotherapy arm Parts A and C, and combination arm Part A, before administration
             of the first DSP-0509 infusion, the patient must be able to provide archival tissue
             with enough nontarget tumor tissue to provide the required number of slides needed for
             baseline assessments, or patient must consent to undergo tumor biopsy to acquire
             sufficient tumor tissue. (Sites need to refer to the current version of the "Tumor
             Collection & Shipment Instructions Manual" to determine how many slides are required
             for each patient. The tissue manual breaks these numbers out based off patient's study
             Arm/Part enrolled to as well as if patient consented to optional future testing).

         14. For monotherapy arm Part B, before administration of the first DSP 0509 infusion, the
             patient must consent to undergo tumor biopsy to acquire sufficient tissue at each of
             the pretreatment and posttreatment evaluations.

         15. For combination arm Part A, the patient must be ICI naïve and have a histologically or
             cytologically confirmed advanced solid tumor that is metastatic or unresectable and
             recurrent and/or refractory to available therapy and is a condition for which
             pembrolizumab is the standard of care treatment. Eligible tumor types for treatment
             with pembrolizumab for combination arm include:

               -  Melanoma

               -  Non-small-cell lung cancer

               -  HNSCC

               -  Urothelial carcinoma

               -  Microsatellite instability-high cancer

               -  Gastric cancer

               -  Cervical cancer

               -  Hepatocellular carcinoma

               -  Merkel cell carcinoma

        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 4 weeks before the first dose of DSP-0509. Local palliative radiotherapy is
             permitted; however, if the radiotherapy is to a target lesion, that lesion must be
             excluded from tumor response assessments.

          3. Receives concurrent systemic (oral or IV) steroid therapy > 10 mg prednisone daily or
             its equivalent for an underlying condition.

          4. Has had major surgery within the 4 weeks before the first dose of DSP-0509.

          5. Has central nervous system (CNS) metastases (including 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 autoimmune disease active or past including but not limited to
             inflammatory bowel disease, systemic lupus erythematosus, ankylosing spondylitis,
             scleroderma, or multiple sclerosis. Has any active 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.

        For enrollment in combination arm only:

        Has a known hypersensitivity to pembrolizumab or its components.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Determine the maximum tolerated dose (MTD) of DSP-0509 by assessing dose-limiting toxicities (DLTs)
Time Frame:4 weeks
Safety Issue:
Description:Monotherapy Arm - Part A (Dose Escalation)

Secondary Outcome Measures

Measure:Evaluate pharmacokinetics (PK) for single agent DSP-0509 by assessing plasma concentration.
Time Frame:8 weeks
Safety Issue:
Description:Monotherapy Arm - Part A (Dose Escalation)
Measure:Objective response rate (ORR) by RECIST
Time Frame:6 months
Safety Issue:
Description:Defined as the proportion of patients with a documented complete response or partial response (CR + PR) based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
Measure:ORR by immune RECIST (iRECIST)
Time Frame:6 months
Safety Issue:
Description:Defined as the proportion of patients with a documented complete response or partial response (CR + PR) based on iRECIST.
Measure:Duration of response (DoR) by RECIST
Time Frame:6 months
Safety Issue:
Description:Defined as the time from first documentation of response until the time of first documentation of disease progression by RECIST v1.1.
Measure:DoR by iRECIST
Time Frame:6 months
Safety Issue:
Description:Defined as the time from first documentation of response until the time of first documentation of disease progression by iRECIST.
Measure:Progression free survival (PFS) by RECIST
Time Frame:12 months
Safety Issue:
Description:Defined as the time from first dose to the earlier date of assessment of progression or death by any cause in the absence of progression by RECIST v1.1.
Measure:PFS by iRECIST
Time Frame:12 months
Safety Issue:
Description:Defined as the time from first dose to the earlier date of assessment of progression or death by any cause in the absence of progression by iRECIST.
Measure:Evaluate single agent DSP-0509-induced changes in cytokine levels.
Time Frame:8 weeks
Safety Issue:
Description:Monotherapy Arm - Part A (Dose Escalation)
Measure:Evaluate change in cytokine levels induced by DSP-0509 in combination with pembrolizumab.
Time Frame:8 weeks
Safety Issue:
Description:Combination Arm - Part A (Dose Escalation)

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Boston Biomedical, Inc

Trial Keywords

  • DSP-0509
  • Toll-Like Receptor 7 (TLR-7)
  • BLRM (Bayesian Logistic Regression Model)

Last Updated

September 30, 2019