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

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ClinicalTrials.gov Identifier: NCT03416335
Recruitment Status : Recruiting
First Posted : January 31, 2018
Last Update Posted : October 2, 2019
Sponsor:
Collaborator:
Syneos Health
Information provided by (Responsible Party):
Boston Biomedical, Inc

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Neoplasms Drug: DSP-0509 Drug: DSP-0509, Pembrolizumab Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 106 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : June 1, 2018
Estimated Primary Completion Date : June 2020
Estimated Study Completion Date : July 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Monotherapy Arm - Part A
Dose Escalation
Drug: DSP-0509
DSP-0509 will be administered as an IV bolus injection over 3 minutes at one of the 5 dose levels being explored in dose escalation (Part A), then at the RP2D in dose expansion (Part B) as well as in maintenance dose schedule evaluation (Part C). The schedule for dosing is DSP-0509 once a week (q1w) for 4 weeks during the induction treatment period (study Day 1 29) followed by dosing every 2 weeks (q2w) during the maintenance treatment period (study Day 30 onwards) with the exception for Part C where the maintenance schedule is changed to every 3 weeks (q3w) in dose-expansion phase.

Experimental: Monotherapy arm - Part B
Dose Expansion
Drug: DSP-0509
DSP-0509 will be administered as an IV bolus injection over 3 minutes at one of the 5 dose levels being explored in dose escalation (Part A), then at the RP2D in dose expansion (Part B) as well as in maintenance dose schedule evaluation (Part C). The schedule for dosing is DSP-0509 once a week (q1w) for 4 weeks during the induction treatment period (study Day 1 29) followed by dosing every 2 weeks (q2w) during the maintenance treatment period (study Day 30 onwards) with the exception for Part C where the maintenance schedule is changed to every 3 weeks (q3w) in dose-expansion phase.

Experimental: Monotherapy arm - Part C
Maintenance Dose Schedule Evaluation
Drug: DSP-0509
DSP-0509 will be administered as an IV bolus injection over 3 minutes at one of the 5 dose levels being explored in dose escalation (Part A), then at the RP2D in dose expansion (Part B) as well as in maintenance dose schedule evaluation (Part C). The schedule for dosing is DSP-0509 once a week (q1w) for 4 weeks during the induction treatment period (study Day 1 29) followed by dosing every 2 weeks (q2w) during the maintenance treatment period (study Day 30 onwards) with the exception for Part C where the maintenance schedule is changed to every 3 weeks (q3w) in dose-expansion phase.

Experimental: Combination arm - Part A
Dose Escalation
Drug: DSP-0509, Pembrolizumab
DSP-0509 will be administered as an IV bolus injection over 3 minutes at one of the 5 dose levels being explored in dose escalation (Part A) and is given in combination with pembrolizumab which should be administered following the dosing schedule of the approved label (200 mg IV q3w)




Primary Outcome Measures :
  1. Determine the maximum tolerated dose (MTD) of DSP-0509 by assessing dose-limiting toxicities (DLTs) [ Time Frame: 4 weeks ]
    Monotherapy Arm - Part A (Dose Escalation)

  2. Determination of the Recommended Phase 2 Dose (RP2D) of DSP-0509 for the Dose Expansion part by assessing dose-limiting toxicities (DLTs) [ Time Frame: 4 weeks ]
    Monotherapy Arm - Part A (Dose Escalation)

  3. Further evaluate the RP2D by monitoring incidence of Adverse Events (AEs), serious AEs (SAEs), and immune-related AEs (irAEs) [ Time Frame: 12 months ]
    Monotherapy Arm - Part B (Dose Expansion): Adverse events will be assessed according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03.

  4. Assess safety and tolerability of DSP-0509 using the RP2D given IV q1w for 4 weeks during induction treatment followed by every 3 weeks (q3w) during maintenance treatment [ Time Frame: 12 months ]
    Monotherapy Arm - Part C (Maintenance Dose Schedule Evaluation)

  5. Determine the MTD of DSP-0509 when given in combination pembrolizumab - by assessing DLTs. [ Time Frame: 4 weeks ]
    Combination arm - Part A (Dose Escalation).

  6. Identify a RP2D of DSP-0509 when given in combination with pembrolizumab - by assessing DLTs [ Time Frame: 4 weeks ]
    Combination arm - Part A (Dose Escalation).


Secondary Outcome Measures :
  1. Evaluate pharmacokinetics (PK) for single agent DSP-0509 by assessing plasma concentration. [ Time Frame: 8 weeks ]
    Monotherapy Arm - Part A (Dose Escalation)

  2. Objective response rate (ORR) by RECIST [ Time Frame: 6 months ]
    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.

  3. ORR by immune RECIST (iRECIST) [ Time Frame: 6 months ]
    Defined as the proportion of patients with a documented complete response or partial response (CR + PR) based on iRECIST.

  4. Duration of response (DoR) by RECIST [ Time Frame: 6 months ]
    Defined as the time from first documentation of response until the time of first documentation of disease progression by RECIST v1.1.

  5. DoR by iRECIST [ Time Frame: 6 months ]
    Defined as the time from first documentation of response until the time of first documentation of disease progression by iRECIST.

  6. Progression free survival (PFS) by RECIST [ Time Frame: 12 months ]
    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.

  7. PFS by iRECIST [ Time Frame: 12 months ]
    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.

  8. Evaluate single agent DSP-0509-induced changes in cytokine levels. [ Time Frame: 8 weeks ]
    Monotherapy Arm - Part A (Dose Escalation)

  9. Evaluate change in cytokine levels induced by DSP-0509 in combination with pembrolizumab. [ Time Frame: 8 weeks ]
    Combination Arm - Part A (Dose Escalation)


Other Outcome Measures:
  1. Identification of potential metabolites of DSP-0509 in plasma and possibly in urine. [ Time Frame: 8 weeks ]
    Monotherapy Arm - Part A (Dose Escalation)

  2. Exploratory pharmacodynamic evaluation as potential biomarkers capable of predicting the clinical efficacy or toxicity [ Time Frame: 12 months ]
  3. Exploratory pharmacodynamic evaluation as potential efficacy-related immune response biomarkers. [ Time Frame: 12 months ]
  4. Evaluate the effect of DSP-0509 on cardiac parameters by assessing continuous 25-hour ECG recordings. [ Time Frame: 12 months ]
    Monotherapy Arm - Part A (Dose Escalation)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03416335


Contacts
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Contact: Boston Biomedical, Inc. 617-674-6800 info@bostonbiomedical.com

Locations
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United States, Indiana
Indiana University Health Melvin and Bren Simon Cancer Center Recruiting
Indianapolis, Indiana, United States, 46202
United States, North Carolina
University of North Carolina at Chapel Hill Recruiting
Chapel Hill, North Carolina, United States, 25799
United States, Pennsylvania
Fox Chase Cancer Center Recruiting
Philadelphia, Pennsylvania, United States, 19111
United States, Tennessee
Henry-Joyce Cancer Center, Vanderbilt University Recruiting
Nashville, Tennessee, United States, 37232
United States, Texas
M.D. Anderson Cancer Center, The University of Texas Recruiting
Houston, Texas, United States, 77030
Sponsors and Collaborators
Boston Biomedical, Inc
Syneos Health

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Responsible Party: Boston Biomedical, Inc
ClinicalTrials.gov Identifier: NCT03416335    
Other Study ID Numbers: BBI-DSP0509-101
First Posted: January 31, 2018    Key Record Dates
Last Update Posted: October 2, 2019
Last Verified: September 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Boston Biomedical, Inc:
DSP-0509
Toll-Like Receptor 7 (TLR-7)
BLRM (Bayesian Logistic Regression Model)
Additional relevant MeSH terms:
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Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents