Evaluation of Safety and Tolerability of TransCon IL-2 β/γ, Pembrolizumab, and TransCon TLR7/8 Agonist in Advanced or Metastatic Solid Tumor Malignancies
- Trial ID
- 2023-509143-27-00
- Protocol
- ASND0029
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **safety** and **tolerability** of TransCon IL-2 β/γ, both as a monotherapy and in combination with pembrolizumab, standard of care (SOC) chemotherapy, or TransCon TLR7/8 Agonist. Additionally, the study aims to define the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of TransCon IL-2 β/γ. This is clinically relevant as it helps determine the optimal dosing regimen for future clinical trials, ensuring patient safety while maximizing therapeutic efficacy in treating locally advanced or metastatic solid tumor malignancies.
Secondary objectives include: - Evaluating the antitumor activity of TransCon IL-2 β/γ alone or in combination with pembrolizumab, SOC chemotherapy, TransCon TLR7/8 Agonist, or SOC trastuzumab or trastuzumab emtansine (T-DM1). - Characterizing the plasma pharmacokinetics (PK) of TransCon IL-2 β/γ and Free IL-2 β/γ, both as monotherapy and in combination with the aforementioned therapies. These objectives are crucial for understanding the drug's behavior in the body and its potential efficacy in different therapeutic combinations.
Participants
The clinical trial involved a total of **297 participants** diagnosed with various **locally advanced or metastatic solid tumor malignancies**, including platinum-resistant ovarian cancer, post-anti-PD-1 melanoma, and HER2+ breast cancer, among others. The study population comprised both male and female subjects, aged 18 years and older, with adequate organ function and an Eastern Cooperative Oncology Group (ECOG) performance status ranging from 0 to 2, depending on the trial part. Participants were selected based on their specific cancer type and treatment history, ensuring they met the criteria for the study's focus on evaluating the safety and tolerability of TransCon IL-2 β/γ, alone or in combination with other therapies. The trial did not include vulnerable populations, and lifestyle factors such as diet and physical activity were not specified as part of the selection criteria. Key inclusion criteria required participants to have measurable disease per RECIST 1.1, and progression on prior therapies was a common requirement across different cohorts.
Plans and Procedures
The clinical trial is designed as a **Phase 1/2, open-label, dose escalation and dose expansion study** to evaluate the safety and tolerability of **TransCon IL-2 β/γ** alone or in combination with **pembrolizumab**, **TransCon TLR7/8 Agonist**, or other anticancer therapies in adult participants with locally advanced or metastatic solid tumor malignancies. The trial aims to define the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of TransCon IL-2 β/γ, both as a monotherapy and in combination with other treatments. The study is expected to conclude by May 8, 2027, with recruitment starting on November 8, 2023.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, organ function, and performance status. The trial includes multiple parts, with each part having specific objectives and endpoints. Follow-up visits will be scheduled to monitor the incidence and severity of adverse events, as well as to evaluate secondary endpoints like objective response rate, progression-free survival, and overall survival. The end-of-study visit will conclude the participant's involvement, summarizing the outcomes and any adverse events experienced.
The expected length of participant involvement varies depending on the part of the trial and the treatment regimen assigned. Participants may be withdrawn from the study early due to reasons such as adverse events, disease progression, or withdrawal of consent. The trial employs a rigorous methodology to ensure the collection of reliable and valid data, contributing to the understanding of the safety and efficacy of the investigational products in treating advanced solid tumors.
Treatment
The clinical trial involves the administration of **TransCon TLR7/8 Agonist**, an experimental medication formulated as a **suspension for injection**. The active substance, ACP-017, is a polymer-based compound developed by Ascendis Pharma Bone Diseases A/S. This medication is administered via **intratumoral use**. The frequency and specific dosing schedule are determined based on the study protocol, with compliance monitored through regular assessments.
Another investigational product in the trial is **TransCon IL-2 β/γ**, which is provided as a **solution for infusion**. The active substance, TransCon IL-2β/γ, is a protein-based compound developed by Ascendis Pharma Oncology Division A/S. This medication is administered through **intravenous infusion**. The dosing regimen is designed to evaluate safety and tolerability, with participant adherence monitored throughout the study.
The trial also includes the use of **KEYTRUDA 25 mg/mL concentrate for solution for infusion**, a non-experimental treatment. The active substance, **pembrolizumab**, is a protein-based compound provided by Merck Sharp & Dohme B.V. This medication is administered via **intravenous infusion**. It serves as a comparator treatment in combination with the investigational products, following a standard dosing schedule as per the approved labeling. Compliance with the administration schedule is closely monitored to ensure accurate data collection.
Efficacy
Efficacy in this clinical trial will be assessed using several key parameters. The primary endpoint focuses on the "Incidence and severity of serious adverse events and adverse events" across all parts of the study. Secondary endpoints include the **Objective Response Rate (ORR)**, **Duration of Response (DoR)**, and **Time to Response (TTR)**, evaluated by both independent central review and investigator assessment, using the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Additionally, **Progression-Free Survival (PFS)** and **Overall Survival (OS)** will be measured. For neoadjuvant cohorts, the ORR prior to surgery, **Pathologic Complete Response (pCR)**, and **Major Pathologic Response (MPR)** will be assessed through central and local pathology reviews. Event-Free Survival (EFS) will also be evaluated using RECIST 1.1 criteria.
The pharmacokinetic parameters of TransCon IL-2 β/γ and Free IL-2 β/γ, both alone and in combination with pembrolizumab, standard of care (SOC) chemotherapy, or TransCon TLR7/8 Agonist, will be analyzed. These assessments will be conducted at specified intervals throughout the trial to ensure comprehensive data collection and analysis. The trial is designed to provide a robust evaluation of the efficacy of the investigational treatments in adult participants with locally advanced or metastatic solid tumor malignancies.
Inclusion and Exclusion Criteria
Inclusion Criteria
- At least 18 years of age or country defined local legal age • Adequate organ function at screening Part 1 and Part 2: Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 Part 3 or Part 4 : ECOG performance status of 0 or 1
- Neoadjuvant Melanoma (Cohorts 6a-c): Cohort Closed to Enrollment • Histologically or cytologically confirmed diagnosis of resectable cutaneous melanoma belonging to one of the following American Joint Committee on Cancer (AJCC) version 8 Tumor Node Metastasis (TNM) stages: Tx or T1-4 and N1b, or N1c, or N2b, or N2c, or N3b, or N3c and M0 • No prior radiotherapy or systemic anticancer therapy for melanoma • For Cohort 6c, participants must have at least one safely accessible lesion for IT injection of TransCon TLR7/8 Agonist that is ≥15 mm in the longest diameter
- Neoadjuvant NSCLC (Cohort 7): • Histologically or cytologically confirmed NSCLC and must be ineligible for known actionable and available targeted therapy (e.g., epidermal growth factor receptor [EGFR]- mutations, anaplastic lymphoma kinase [ALK] rearrangement, or ROS1 rearrangements, or BRAF V600E mutation) and with completely resectable disease (tumors ≥4 cm or node positive) • No prior radiotherapy or systemic anticancer therapy for NSCLC • Evaluable disease with at least 1 measurable target lesion per RECIST 1.1 criteria
- Post anti-PD-(L)1 NSCLC (Cohort 8): • Histologically or cytologically confirmed diagnosis of metastatic (stage IV) squamous or nonsquamous NSCLC • Must have progression of disease following treatment with platinum-based chemotherapy in addition to anti-PD(L)-1. • Must have received or be ineligible for known actionable and available targeted therapy (e.g., EGFR mutations, ALK rearrangement, ROS rearrangement, or BRAF V600E mutation). • Progression must be determined according to RECIST 1.1 while on anti-PD-(L)1 therapy or within 3 months of the last dose of anti-PD-(L)1 therapy • At least 1 target lesion of measurable disease per RECIST 1.1
- Post anti-PD-(L)1 SCLC (Cohort 9): • Histologically or cytologically confirmed diagnosis of extensive stage SCLC. • Must have progression of disease following treatment with platinum-based chemotherapy in addition to anti-PD-(L)1. • Progression must be determined according to RECIST 1.1 while on anti-PD-(L)1 therapy or within 3 months of the last dose of anti-PD-(L)1 therapy. • At least 1 target lesion of measurable disease per RECIST 1.1.
- 3L+ PROC (Cohort 14): TransCon IL-2 β/γ plus SOC Paclitaxel, Step-up RP2D Dosing: • Female participants with histologic or cytologic documentation of epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. • Must have PROC, defined as cancer progression within 6 months after completion of prior platinum-based therapy (at least 3 cycles). • Have received at least 2 lines of systemic therapy for ovarian cancer, including at least one platinum-based therapy. • At least 1 measurable target lesion as per RECIST 1.1.
- 3L+ PROC (Cohort 15): TransCon IL-2 β/γ Monotherapy, Step-up RP2D Dosing • Female participants with histologic or cytologic documentation of epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. Carcinosarcoma, sarcoma, mucinous ovarian cancer, or low grade serous histologies are excluded. • Must have PROC, defined as cancer progression within 6 months after completion of prior platinum-based therapy (at least 3 cycles). Progression is defined by RECIST 1.1 criteria in association with symptoms necessitating treatment. • Have received at least 2 lines of systemic therapy for ovarian cancer, including at least one platinum-based therapy. • At least 1 measurable target lesion as per RECIST 1.1.
- Post Anti-PD-1 Melanoma (Cohort 10): Cohort Closed to Enrollment • Must have unresectable (stage III) or metastatic (stage IV) melanoma who have progressed on anti-PD-1 therapy or had recurrence <6 months after adjuvant anti-PD-1 therapy • Progression must be determined according to RECIST 1.1 while on anti-PD-1 therapy or within 3 months of the last dose of anti-PD-1 therapy • At least 1 target lesion of measurable disease per RECIST 1.1
- Metastatic Breast Cancer (Cohort 11) • Must have HER2+ metastatic breast cancer as defined by current American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) or local guidelines. • Have received at least 2 lines of anti-HER2 targeted therapies for metastatic disease setting • At least 1 target lesion of measurable disease per RECIST 1.1
- Metastatic Breast Cancer (Cohort 12) • Must have HER2+ metastatic breast cancer as defined by current ASCO/CAP or local guidelines • Have received at least 2 lines of anti-HER2 targeted therapies for metastatic disease setting • At least 1 target lesion of measurable disease per RECIST 1.1
- Metastatic Cervical Cancer (Cohort 13) • Must have extra-pelvic metastatic or recurrent cervical cancer with squamous cell, adenocarcinoma or adenosquamous histology, who are not candidates for curative therapy • Have received at least 1, but no more than 2 prior systemic treatment regimens for recurrent or metastatic cervical cancer. Chemotherapy administered in the adjuvant or neoadjuvant setting, or in combination with radiation therapy should not be counted as a prior systemic treatment regimen for recurrent or metastatic disease • At least 1 target lesion of measurable disease per RECIST 1.1
- Part 2 and Part 4: • Tumor types where there is expected clinical activity of pembrolizumab in the advanced treatment setting and where participation in this clinical study is deemed by the investigator to be in the best interest of the participant compared to any other available therapies • No more than 2 lines of therapy or treatment regimens for locally advanced, unresectable, recurrent or metastatic disease
- PROC (Cohort 3): Cohort Closed to Enrollment • Female participants with histologic or cytologic documentation of epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer • Must have PROC platinum-resistant ovarian cancer , defined as cancer progression within 6 months after completion of prior platinum-based therapy (at least 3 cycles) • At least 1 target lesion of measurable disease per RECIST 1.1
- Post-PD-1 Melanoma (Cohort 4): Cohort Closed to Enrollment • Must have unresectable (stage III) or metastatic (stage IV) melanoma who have progressed on anti-PD-1 therapy or had recurrence <6 months after adjuvant anti-PD-1 therapy • Progression must be determined according to RECIST 1.1 while on anti-PD-1 therapy or within 3 months of the last dose of anti-PD-1 therapy • At least 1 target lesion of measurable disease per RECIST 1.1 and at least one safely accessible lesion for IT injection of TransCon TLR7/8 Agonist that is ≥15 mm in the longest diameter
- Metastatic Cervical Cancer (Cohort 5): Cohort Closed to Enrollment • Must have extra-pelvic metastatic or recurrent cervical cancer with squamous cell, adenocarcinoma or adenosquamous histology, who are not candidates for curative therapy • Have received at least 1, but no more than 2 prior systemic treatment regimens for recurrent or metastatic cervical cancer. Chemotherapy administered in the adjuvant or neoadjuvant setting, or in combination with radiation therapy should not be counted as a prior systemic treatment regimen for recurrent or metastatic disease • At least 1 target lesion of measurable disease per RECIST 1.1
- Post Anti-PD-1 Melanoma (Cohort 16): TransCon IL-2 β/γ Monotherapy, Step-up RP2D Dosing) • Histologically or cytologically confirmed diagnosis of unresectable (stage III) or metastatic (stage IV) melanoma who have progressed on anti-PD-1 therapy or had recurrence ≤12 weeks after adjuvant anti-PD-1 therapy. Acral/lentiginous and uveal melanoma are excluded. • Progression is defined as follows: 1. Required to have disease that has progressed on anti-PD-1, anti-lymphocyte activation gene 3 (LAG3), and anti-CTLA-4, either in combination(s) or sequentially (unless clinically contraindicated as deemed by the treating clinician or if not available locally). .2. Progression must be determined according to RECIST 1.1 while on anti PD 1 therapy or within 3 months of the last dose of anti-PD-1 therapy. • If participant is known to have BRAF-mutated disease, participant must have progressed on prior BRAF/MEK-directed therapy unless deemed clinically contraindicated by the treating clinician. • Have Stage III unresectable, M1a, or M1b disease per AJCC v8 (participants with M1c or M1d disease are not eligible). 1. M1a: distant metastasis to skin, soft tissue including muscles, and/or nonregional lymph nodes. 2. M1b: distant metastasis to lung with or without M1a sites of disease • Have had no more than 3 prior lines of therapy in the locally advanced unresectable or metastatic setting.
Exclusion Criteria
- Prior treatment with IL-2 and variants (all participants) or TLR agonist (Part 3, Cohorts 4, 5, and 6c only) • Active autoimmune conditions • Significant cardiac disease • Symptomatic central nervous system metastases
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 08 Nov 2023 | 5 |
 Italy | Not Recruiting | 08 Nov 2023 | 50 |
 Poland | Not Recruiting | 08 Nov 2023 | 15 |
 Spain | Not Recruiting | 08 Nov 2023 | 50 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
TransCon TLR7/8 Agonist | Test | SUSPENSION FOR INJECTION | INTRATUMORAL USE | — | — | PRD9278735 |
TransCon IL-2 ß/ү | Test | SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | — | — | PRD10820825 |
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | — | — | PRD4323105 |