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

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

To evaluate MEDI9197 when administered by intratumoral injection to subjects with solid tumors and in combination with durvalumab in subjects with solid tumors.

Study Overview

• Status: Terminated
• Conditions: Cancer; Solid Tumors; CTCL
• Intervention / Treatment: Drug: MEDI9197; Biological: durvalumab

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
• Enrollment (Actual): 53
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1Z6
      • Research Site
• France
  • Villejuif, France, 94805
    • Research Site
• United States
  • California
    • San Francisco, California, United States, 94115
      • Research Site
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Research Site
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Research Site
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Research Site
  • New York
    • New York, New York, United States, 10029
      • Research Site
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-7305
      • Research Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Research Site
  • Texas
    • Houston, Texas, United States, 77030
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Escalation MEDI9197; MEDI9197	Drug: MEDI9197; Subjects will receive MEDI9197 (every 4 weeks) as monotherapy (or MEDI9197 every 8 weeks + durvalumab every 4 weeks)(PA6)
Experimental: Escalation MEDI9197 with durvalumab; MEDI9197 in combination with durvalumab	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 Names: MEDI4736
Experimental: Escalation MEDI9197 durvalumab radiation; MEDI9197 in combination with durvalumab and palliative radiation	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 Names: MEDI4736
Experimental: MEDI9197 with palliative radiation; MEDI9197 in combination with palliative radiation	Drug: MEDI9197; Subjects will receive MEDI9197 (every 4 weeks) as monotherapy (or MEDI9197 every 8 weeks + durvalumab every 4 weeks)(PA6)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	The primary endpoint will be the number (%) of subjects with dose-limiting toxicities, adverse and serious adverse events and other safety parameters.	From time of informed consent through 4 weeks after last dose of investigational product
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	The primary endpoint will be the number (%) of subjects with dose-limiting toxicities, adverse and serious adverse events and other safety parameters.	From time of informed consent through 6 months after last dose of investigational product
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.	The primary endpoint will be the number (%) of subjects with dose-limiting toxicities, adverse and serious adverse events and other safety parameters.	From time of informed consent through 90 days after last dose of investigational product

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: MedImmune LLC

Publications and helpful links

General 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.

Study record dates

Study Major Dates

• Study Start (Actual): November 4, 2015
• Primary Completion (Actual): October 26, 2018
• Study Completion (Actual): October 26, 2018

Study Registration Dates

• First Submitted: September 1, 2015
• First Submitted That Met QC Criteria: September 21, 2015
• First Posted (Estimate): September 22, 2015

Study Record Updates

• Last Update Posted (Actual): December 19, 2018
• Last Update Submitted That Met QC Criteria: December 14, 2018
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Keywords: Durvalumab; MEDI4736; MEDI9197; TLR 7/8 Agonist; Imfinzi
• Additional Relevant MeSH Terms: Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Adjuvants, Immunologic; Durvalumab; MEDI9197
• Other Study ID Numbers: D6410C00001