A Study of MEDI9197 in Subjects With Solid Tumors or CTCL and in Combination With Durvalumab and/or Palliative Radiation in Subjects With Solid Tumors

• ClinicalTrials.gov Identifier: NCT02556463
• Recruitment Status: Terminated
• First Posted: September 22, 2015
• Last Update Posted: December 19, 2018
• Sponsor: MedImmune LLC
• Information provided by (Responsible Party): MedImmune LLC

Tracking Information

• First Submitted Date: September 1, 2015
• First Posted Date: September 22, 2015
• Last Update Posted Date: December 19, 2018
• Actual Study Start Date: November 4, 2015
• Actual Primary Completion Date: October 26, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 8, 2017)

• Safety and tolerability as determined by assessment of dose limiting toxicities and the maximum tolerated dose or maximal assessed dose per protocol of MEDI9197 when administered by intratumoral injection to subjects with solid tumor cancers [ Time Frame: From time of informed consent through 4 weeks after last dose of investigational product ]
  The primary endpoint will be the number (%) of subjects with dose-limiting toxicities, adverse and serious adverse events and other safety parameters.
• Safety and tolerability as determined by assessment of dose limiting toxicities and the maximum tolerated dose or maximal assessed dose per protocol of MEDI9197 when administered by intratumoral injection to subjects with CTCL [ Time Frame: From time of informed consent through 6 months after last dose of investigational product ]
  The primary endpoint will be the number (%) of subjects with dose-limiting toxicities, adverse and serious adverse events and other safety parameters.
• Safety & tolerability as determined by dose limiting toxicities and maximum tolerated or assessed dose of MEDI9197 administered by IT injection in combo with durvalumab and durvalumab plus palliative radiation to subjects with solid tumor cancers. [ Time Frame: From time of informed consent through 90 days after last dose of investigational product ]
  The primary endpoint will be the number (%) of subjects with dose-limiting toxicities, adverse and serious adverse events and other safety parameters.

Original Primary Outcome Measures (submitted: September 21, 2015)

Safety and Tolerability of the Maximum Tolerated or Maximal Assessed Dose as measured by data including but not limited to subject incidence of AEs as assessed by CTCAE v4.03, laboratory tests toxicity, treatment exposure, and PK/PD [ Time Frame: From time of informed consent through 8 weeks after last dose of investigational product ]

The primary endpoint will be the number (%) of subjects with dose limiting toxicities, adverse and serious adverse events and other safety parameters.

Current Secondary Outcome Measures (submitted: December 14, 2018)

• The maximum concentration of MEDI9197 after the first injection [ Time Frame: Pre-dose to 24 hours post first dose ]
• The apparent terminal half-life of MEDI9197 [ Time Frame: Pre-dose to 24 hours post first dose ]
• Percent change from baseline in cluster of differentiation 8 tumor infiltrating lymphocytes in tumor tissue [ Time Frame: Baseline to Day 50 ]
• Percent change from baseline in serum inflammatory cytokine levels [ Time Frame: Pre-dose to end of study, up to 24 months ]
• Percent change from baseline in tumor measurements [ Time Frame: Pre-dose to disease progression, up to 12 months ]
• Objective response rate [ Time Frame: Pre-dose to end of study, up to 24 months ]
• Duration of response [ Time Frame: Pre-dose to end of study, up to 24 months ]
• Percent change from baseline in CAILDS for subjects with CTCL [ Time Frame: Pre-dose to disease progression, up to 12 months ]
• Percent change from baseline in mSWAT scored for subjects with CTCL [ Time Frame: Pre-dose to disease progression, up to 12 months ]
• Percent change from baseline in Investigator Global Assessment (IGA) for subjects with CTCL [ Time Frame: Pre-dose to disease progression, up to 12 months ]
• Percent change from baseline in Subject Global Assessment (SGA) for subjects with CTCL [ Time Frame: Pre-dose to disease progression, up to 12 months ]

Original Secondary Outcome Measures (submitted: September 21, 2015)

• Pharmacokinetics of MEDI9197: Individual Concentrations of MEDI9197 [ Time Frame: Multiple Timepoints up until Day 113 ]
  The endpoints for assessment of MEDI9197 include individual subject MEDI9197 concentrations in serum at different timepoints after MEDI9197 administration.
• Pharmacokinetics of MEDI9197: Noncompartmental PK data analysis - Maximum Observed Concentration [Cmax] [ Time Frame: Multiple Timepoints up until Day 113 ]
  If data permits, noncompartmental PK data analysis will be performed for each cohort including the following PK Parameter - Maximum Observed Concentration [Cmax]
• Pharmacokinetics of MEDI9197: Noncompartmental PK data analysis - Time of Maximum Concentration [Tmax] [ Time Frame: Multiple Timepoints up until Day 113 ]
  If data permits, noncompartmental PK data analysis will be performed for each cohort including the following PK Parameter - Time of Maximum Concentration [Tmax]
• Pharmacokinetics of MEDI9197: Noncompartmental PK data analysis - Area Under the Concentration Time Curve [AUC] [ Time Frame: Multiple Timepoints up until Day 113 ]
  If data permits, noncompartmental PK data analysis will be performed for each cohort including the following PK Parameter - Area Under the Concentration Time Curve [AUC]
• Pharmacokinetics of MEDI9197: Noncompartmental PK data analysis - Terminal Elimination Half-Life [ Time Frame: Multiple Timepoints up until Day 113 ]
  If data permits, noncompartmental PK data analysis will be performed for each cohort including the following PK Parameter - Terminal Elimination Half-Life
• Preliminary Antitumor Activity: Duration of Response [ Time Frame: At approximately 4 timepoints up until Day 141 ]
  The endpoints for the assessment of antitumor activity include Duration of Response (DoR) and is defined for responders as the period from the first documentation of objective response to the first documented disease progression per RECIST v1.1)
• Preliminary Antitumor Activity: Disease Control [ Time Frame: At approximately 4 timepoints up until Day 141 ]
  The endpoints for the assessment of antitumor activity include Disease Control and is defined as best overall response of CR, PR, SD according to RECIST v1.1
• Preliminary Antitumor Activity: Objective Response [ Time Frame: At approximately 4 timepoints up until Day 141 ]
  The endpoints for the assessment of antitumor activity include objective response (OR) and is defined as the best overall response according to RECIST 1.1
• Biomarker Activity: Intratumoral PD biomarkers including changes from baseline levels in various lymphocyte populations. [ Time Frame: At multiple timepoints through Day 141 ]
  The assessment of selected biomarker values will include descriptive statistics for change from baseline
• Biomarker Activity: Systemic PD parameters including changes from baseline plasma protein levels in various inflammatory cytokines. [ Time Frame: At multiple timepoints through Day 141 ]
  The assessment of selected biomarker values will include descriptive statistics for change from baseline
• Biomarker Activity: Intratumoral PD biomarkers including changes from baseline in gene expression profiles for various immune parameters. [ Time Frame: At multiple timepoints through Day 141 ]
  The assessment of selected biomarker values will include descriptive statistics for change from baseline

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of MEDI9197 in Subjects With Solid Tumors or CTCL and in Combination With Durvalumab and/or Palliative Radiation in Subjects With Solid Tumors
• Official Title: A Phase I, First-Time-in-Human Study of MEDI9197, a TLR 7/8 Agonist, Administered Intratumorally as a Single Agent in Subjects With Solid Tumors or CTCL and in Combination With Durvalumab and/or Palliative Radiation in Subjects With Solid Tumors
• Brief Summary: To evaluate MEDI9197 when administered by intratumoral injection to subjects with solid tumors and in combination with durvalumab in subjects with solid tumors.
• Detailed Description: This is a multicenter, open-label study to evaluate the TLR 7/8 agonist MEDI9197 delivered by IT injection to subjects with solid tumors and in combination with durvalumab in subjects with solid tumors. The study has a dose escalation design using mTPI-2 to evaluate a range of doses.
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Solid Tumors
• CTCL
• Cancer

Intervention

• Drug: MEDI9197
  Subjects will receive MEDI9197 (every 4 weeks) as monotherapy (or MEDI9197 every 8 weeks + durvalumab every 4 weeks)(PA6)
• Biological: durvalumab
  Subjects will receive durvalumab every 4 weeks
  Other Name: MEDI4736

Study Arms

• Experimental: Escalation MEDI9197
  MEDI9197
  Intervention: Drug: MEDI9197
• Experimental: Escalation MEDI9197 with durvalumab
  MEDI9197 in combination with durvalumab
  Interventions:

  • Drug: MEDI9197
  • Biological: durvalumab
• Experimental: Escalation MEDI9197 durvalumab radiation
  MEDI9197 in combination with durvalumab and palliative radiation
  Interventions:

  • Drug: MEDI9197
  • Biological: durvalumab
• Experimental: MEDI9197 with palliative radiation
  MEDI9197 in combination with palliative radiation
  Intervention: Drug: MEDI9197

• Publications *: Siu L, Brody J, Gupta S, Marabelle A, Jimeno A, Munster P, Grilley-Olson J, Rook AH, Hollebecque A, Wong RKS, Welsh JW, Wu Y, Morehouse C, Hamid O, Walcott F, Cooper ZA, Kumar R, Ferte C, Hong DS. Safety and clinical activity of intratumoral MEDI9197 alone and in combination with durvalumab and/or palliative radiation therapy in patients with advanced solid tumors. J Immunother Cancer. 2020 Oct;8(2):e001095. doi: 10.1136/jitc-2020-001095.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: December 14, 2018): 53
• Original Estimated Enrollment (submitted: September 21, 2015): 45
• Actual Study Completion Date: October 26, 2018
• Actual Primary Completion Date: October 26, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria for All Subjects (Parts 1, 2 and 3)

1. Written informed consent and any locally required authorizations.
2. Male and female subjects at least 18 years at the time of screening.
3. Adequate organ function within 14 days of enrollment confirmed by laboratory results.
4. Systemic corticosteroids at doses exceeding 12 mg/day prednisone or equivalent.
5. ECOG 0 or 1.
6. Highly effective method of contraception from the date of the screening pregnancy test, and continued precautions for 6 months after the final dose of investigational product.
7. Baseline Child-Pugh Score of A1 to B7.
8. Life expectancy ≥ 12 weeks, as estimated by Royal Marsden Hospital Score of 0 or 1 at baseline.

9. Subjects with hepatocellular carcinoma (HCC) are eligible if the tumor is defined as nodular type 1 or 2 only.

   Additional Inclusion Criteria for Subjects in Parts 1 and 3

10. Metastatic/locally advanced solid tumor malignancy that has progressed on, is refractory to, or for which there is no standard of care therapy.
11. For subjects with cutaneous/subcutaneous lesions, subjects must have more than one measurable target lesion, at baseline, with a minimum of one lesion that meets protocol specified criteria.

12. For subjects with deep-seated lesions, subjects must have more than one measurable target lesion at baseline (RECIST v1.1), with a minimum of one deep-seated lesion suitable for image-guided injection and that meets protocol specified criteria.

    Additional Inclusion Criteria for Subjects in Part 2 (Closed to Enrollment as of Protocol Amendment 6)

13. Clinical diagnosis of CTCL, including documentation of a skin biopsy with histological findings consistent with CTCL or unconfirmed diagnosis of CTCL with confirmation biopsy at screening.
14. Stage IB, IIA, or IIB disease: T1, T2 or T3 (patches, plaques or tumors) with measurable lesions.
15. Previous treatment with at least one standard therapy used to treat the stage of disease at study entry; Stage IB, IIA or IIB CTCL.
16. Measurable skin disease with at least 2 lesions amenable to response assessment.
17. At least one lesion must be amenable to injection, ie, ≥ 1.5 cm in the longest diameter.

Exclusion Criteria:

Any of the following would exclude the subject from participation in the study:

1. Subjects who have received prior immunotherapy [(including but not limited to CTLA-4, oncolytic virus, oncolytic peptide-all require 100 day washout), programmed death ligand (PDL)-1, or programmed cell death 1 antagonists-both require 14 day washout)] are NOT permitted to enroll, with protocol exceptions.
2. Pregnant or lactating.
3. Active bacterial, fungal, or viral infections, including chronic or active hepatitis B, chronic or active hepatitis C, or active hepatitis A. Prior documented infections must have resolved.
4. Active or prior documented autoimmune or inflammatory disorders, with exceptions per protocol. Includes known allergy to sesame oil and/or nuts.
5. Immune-deficiency states - myelodysplastic disorders, marrow failures, human immunodeficiency virus (HIV) infection, history of solid organ transplant or bone marrow allograft, or recent pregnancy.
6. Requires continuous (daily) anticoagulation or antiplatelet therapy (including anti aggregants), acetylsalicylic acid (ASA) or nonsteroidal anti-inflammatory drugs (NSAIDs).
7. History of coagulopathy resulting in uncontrolled bleeding or other bleeding disorders.
8. Rapidly progressing disease per protocol.
9. Untreated or uncontrolled central nervous system (CNS) involvement.
10. Any concurrent chemotherapy, immunotherapy, or biologic or hormonal therapy for cancer treatment; with exceptions per protocol.
11. Unresolved toxicities from prior anticancer therapy, defined as having not resolved to NCI CTCAE v4.03 Grade 0 or 1, with exception of alopecia, vitiligo.
12. Uncontrolled concurrent illness.
13. Cardiac exclusions: New York Heart Association Class 3 or 4 congestive heart failure, uncontrolled hypertension, acute coronary syndrome within 6 months, clinical important cardiac arrhythmia, mean QTC interval corrected for heart rate >500ms.
14. Major surgery within 4 weeks prior to study entry or still recovering from prior surgery.
15. Receipt of live, attenuated vaccine within 28 days prior to study entry.
16. Receipt of any systemic anticancer therapy not mentioned above within the last 2 weeks or 5 half-lives.
17. Cognitive disorder such that informed consent cannot be obtained directly from the subject
18. Subjects who have previously participated in this study and received MEDI9197, or concurrent enrollment in another clinical study involving an investigational treatment.
19. Subjects who have received prior TLR agonists, both systemic and topical.
20. Patients who have received prior therapeutic radiation within 28 days of dosing. All toxicities from prior radiotherapy must have resolved to ≤ Grade 1 or baseline prior to dosing.
21. Body weight < 35 kg
22. Subjects enrolling in Part 3 (ie, receiving durvalumab) must not have a history of interstitial lung disease or pneumonitis.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 99 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, France, United States

Administrative Information

• NCT Number: NCT02556463
• Other Study ID Numbers: D6410C00001
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: MedImmune LLC
• Original Responsible Party: Same as current
• Current Study Sponsor: MedImmune LLC
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: MedImmune LLC; MedImmune LLC

• PRS Account: MedImmune LLC
• Verification Date: December 2018