T-regulatory Cell Depletion with E7777 Combined with Pembrolizumab in Recurrent or Metastatic Solid Tumors

NCT05200559 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: HCC 21-166
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 1

Brief Summary

Epithelial ovarian cancer (OC) is the most lethal gynecologic cancer: nearly 22,000 women are diagnosed with OC in the US annually and 63% are expected to die from their disease. The 5-year overall survival rate is unacceptably low at 20-30%, with \> 50% of patients experiencing recurrence of their disease. Recurrent, platinum-resistant OC is characterized by a low response to chemotherapy (\<10-15%) and poor prognosis, with overall survival estimated to be \<12 months. Thus, there is an urgent need to identify novel therapies to improve outcomes for patients with recurrent, platinum resistant OC. The primary focus in this trial is targeting tumor associated immunosuppressive T-regs with E7777 combined with PD-1 inhibitor, pembrolizumab. This trial will enroll patients with solid tumors in the dose escalation portion and specified cohorts in the dose expansion portion. In the Phase I portion, 18-30 patients will be enrolled. In the dose expansion portion, approximately 40 patients (20 in each cohort) will be enrolled. Given the relatively poor prognosis and limited treatment options for these patients, this population is considered appropriate for trials of novel therapeutic candidates.

Conditions

Epithelial Ovarian Cancer

Keywords

PD1/PD-L1-based immunotherapy; Immune Checkpoint Inhibitors (ICI); High Microsatellite Instability (MSI-H); Mismatch Repair Deficiency (dMMR)

Outcome Measures

Primary Outcomes (7)

• Recommended Phase 2 Dose (RP2D)

  Dose-limiting toxicities (DLT) related to E7777 with the immune checkpoint inhibitor (ICI), pembrolizumab. DLT per CTCAE v5.0 will be assessed to determine the RP2D of the treatment combination. Up to twenty patients will be evaluated for DLTs during each dose levels for first 2 cycles (42 days). The transition to next dose level will be determined and planned based on the review of the data on the prior dose level. Safety will be assessed by DLTs, as well as the frequency and severity of immune and non-immune mediated adverse events. or a treatment-related toxicity of any grade requiring dose delay of 3 weeks or more between the first and second cycles

  Up to 12 months (cohort)

• Change in T-regulatory cells in tumor

  Change in levels of T-regulatory cells within the immune microenvironment of tumors.

  Up to 5 years

• Change in CD8+ T cells in tumor

  Change in levels of CD8+ T cells within the immune microenvironment of tumors.

  Up to 5 years

• Change in myeloid cells in tumor

  Change in levels of myeloid cells within the immune microenvironment of tumors.

  Up to 5 years

• Change in T-regulatory cells - peripheral blood

  Change in T-regulatory cells within the immune microenvironment of peripheral blood.

  Up to 5 years

• Change in CD8+ T cells - peripheral blood

  Change in levels of CD8+ T cells within the immune microenvironment of peripheral blood.

  Up to 5 years

• Change in myeloid cells in peripheral blood

  Change in levels of myeloid cells within the immune microenvironment of peripheral blood.

  Up to 5 years

Secondary Outcomes (3)

• Objective Response

  Up to 5 years

• Progression-free survival (PFS)

  Up to 5 years

• Overall survival (OS)

  Up to 5 years

Study Arms (1)

E7777 + Pembrolizumab

EXPERIMENTAL

Phase l: E7777: Dose Level 1, 3 µg/kg; Dose Level 2, 6 µg/kg; Dose Level 3, 9 µg/kg; Dose Level 4, 12 µg/kg Day 1-3 - given up to 8 cycles (dose-limiting toxicities assessed for first two cycles, only) Pembrolizumab: 200 mg, IV on Day 1 (21-day cycle) Phase ll: E7777: administered on Day 1-3 at Phase 2 Recommended Dose (P2RD); Day 1-3 up to 8 cycles Pembrolizumab: 200 mg, IV on Day 1 (21-day cycle)

Drug: Pembrolizumab; Drug: E7777

Interventions

Pembrolizumab DRUG

Pembrolizumab is a humanized monoclonal immunoglobulin (Ig) G4 antibody that inhibits lymphocytes PD-1 receptors, blocking the ligands that would deactivate it and prevent an immune response, allowing the immune system to target and destroy cancer cells.

Also known as: Keytruda®

E7777 + Pembrolizumab

E7777 DRUG

E7777 or denileukin diftitox is a recombinant cytotoxic fusion protein composed of the amino acid sequences for diphtheria toxin fragments A and B (Met1-Thr387)-His and for human interleukin-2 (Ala1-Thr133), indicated for the treatment of patients with persistent or recurrent cutaneous T-cell lymphoma (CTCL) whose malignant cells express the CD25 component of the IL-2 receptor.

Also known as: ONTAK®

E7777 + Pembrolizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Ability to comply with the study protocol, in the investigator's judgment
• Histologically or cytologically confirmed solid tumors (cutaneous melanoma, non-small cell lung cancer, renal cell carcinoma, endometrial cancer, ovarian cancer, MSI-H solid tumors (deficient mismatch repair system or other solid tumors) that have progressed on or refractory to standard of care therapies for their disease
• Phase I dose escalation phase
• Advanced metastatic or recurrent solid tumors (where pembrolizumab is approved and/or have shown efficacy) that have progressed on or refractory to standard of care therapies for their disease
• Prior anti-PD1 or PDL1 therapy is allowed
• Prior anti-CTLA4 therapy is allowed if had anti-CTLA4 free interval of 6 months or more
• At least one prior line of therapy in the dose escalation phase
• Phase Ib dose expansion cohorts
• Platinum-resistant recurrent ovarian cancer (recurred within 6 months or less of prior platinum therapy) or post-PD1/PDL1 MSI-H cancers (mismatch repair deficient tumors). Patients in the ovarian cancer cohort must have received chemotherapy plus bevacizumab unless bevacizumab is contra-indicated or considered risky per treating physician.
• Prior 1-5 lines of therapy for dose expansion
• Prior anti-PD1/PDL1 therapy is allowed in the MSI-H cohort but not in the ovarian cohort
• Prior anti-CTLA4 therapy is not allowed.
• Primary platinum- refractory cancers are excluded in the dose expansion (progressed during or within 3 months of primary platinum therapy)
• Measurable disease per RECIST v1.1
• o Previously irradiated lesions can be considered as measurable disease only if progressive disease has been unequivocally documented at that site since radiation.

You may not qualify if:

• Patients who meet any of the following criteria will be excluded from study entry:
• History of leptomeningeal disease. Patients with brain metastasis are allowed if their brain metastasis was adequately treated with surgery or radiation or both, have been stable for at least 6 months and not on steroids.
• Uncontrolled tumor-related pain
• Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement) amenable to palliative radiotherapy should be treated prior to enrollment. Patients should be recovered from the effects of radiation. There is no required minimum recovery period.
• Asymptomatic metastatic lesions that would likely cause functional deficits or intractable pain with further growth (e.g., epidural metastasis that is not currently associated with spinal cord compression) should be considered for loco-regional therapy if appropriate prior to enrollment.
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently)
• o Patients with indwelling catheters (e.g., PleurX™) are allowed.
• Uncontrolled or symptomatic hypercalcemia (ionized calcium \> 1.5 mmol/L, calcium \> 12 mg/dL or corrected serum calcium \> ULN)
• Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis for a more comprehensive list of autoimmune diseases and immune deficiencies), with the following exceptions:
• Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study.
• Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.
• Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met:
• Rash must cover \< 10% of body surface area
• Disease is well controlled at baseline and requires only low-potency topical corticosteroids
• No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months

Sponsors & Collaborators

• Alexander B Olawaiye, MD: lead
• Dr. Reddys Laboratories, SA: collaborator

Study Sites (1)

UPMC Hillman Cancer Center

Pittsburgh, Pennsylvania, 15232, United States

RECRUITING

Related Publications (1)

• Mahdi HS, Woodall-Jappe M, Singh P, Czuczman MS. Targeting regulatory T cells by E7777 enhances CD8 T-cell-mediated anti-tumor activity and extends survival benefit of anti-PD-1 in solid tumor models. Front Immunol. 2023 Oct 27;14:1268979. doi: 10.3389/fimmu.2023.1268979. eCollection 2023.

  PMID: 38022532 DERIVED

MeSH Terms

Conditions

Carcinoma, Ovarian Epithelial; Turcot syndrome

Interventions

pembrolizumab; E7777 fusion protein; denileukin diftitox

Condition Hierarchy (Ancestors)

Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Ovarian Neoplasms; Endocrine Gland Neoplasms; Neoplasms by Site; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Endocrine System Diseases; Gonadal Disorders

Study Officials

• Alexander Olawaiye, MD

  UPMC Hillman Cancer Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Kelsey Mitch, RN

CONTACT

412-648-6417; adamikka2@upmc.edu

Lucia Borasso, RN

CONTACT

4126413304; borrlm@upmc.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor of Medicine

Study Record Dates

• First Submitted: January 5, 2022
• First Posted: January 20, 2022
• Study Start: September 30, 2022
• Primary Completion: December 1, 2025
• Study Completion (Estimated): December 1, 2027
• Last Updated: December 5, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)