Advanced Solid Tumor, Locally Advanced Solid Tumor, Metastatic Solid Tumor, Platinum-resistant Ovarian Cancer, Post Anti-PD-1 Melanoma, 2L+ Cervical Cancer, Neoadjuvant Melanoma, Neoadjuvant Non-Small Cell Lung Cancer, Post Anti-PD-(L)1 Non-Small Cell Lung Cancer, Post Anti-PD-(L)1 Small Cell Lung Cancer, Third Line or Later (3L+) HER2+ Breast Cancer, Second or Third Line (2L/3L) Cervical Cancer, Third-line or Later (3L+) Platinum-resistant Ovarian Cancer (PROC)
Conditions
Brief summary
TransCon IL-2 β/γ is an investigational drug being developed for treatment of locally advanced or metastatic solid tumors. This is a first-in-human, open-label, Phase 1/2, dose escalation and dose expansion study of TransCon IL-2 β/γ as monotherapy or in combination therapy in adult participants with advanced or metastatic solid tumors. Given the unique PK profile enabled by the TransCon technology, TransCon IL-2 β/γ presents the opportunity to enhance the therapeutic index of current IL-2 therapy.
Detailed description
IL-2 is a key cytokine that directs the immune system through pleiotropic effects mediated by promoting expansion of both cytotoxic effector cells and Tregs. TransCon IL-2 β/γ is designed as a long-acting delivery prodrug of IL-2 β/γ, a potent cytokine signaling molecule, with the potential to improve the safety and efficacy of IL-2.
Interventions
TransCon IL-2 β/γ will be administered as an intravenous (IV) infusion
DRUGPembrolizumab
Pembrolizumab will be administered as an intravenous (IV) infusion
DRUGChemotherapy drug
SOC chemotherapy will be administered as an intravenous (IV) infusion
TransCon TLR7/8 Agonist will be administered as an IT (Intratumoral) injection
PROCEDURESurgery
Surgery will take place 4-6 weeks after last dose of study treatment.
DRUGTrastuzumab
Trastuzumab will be administered as an intravenous (IV) infusion
Trastuzumab emtansine (T-DM1) will be administered as an intravenous (IV) infusion
Sponsors
Ascendis Pharma Oncology Division A/S
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * At least 18 years of age, or country defined local legal age * Demonstrated adequate organ function at screening * Life expectancy \>12 weeks as determined by the Investigator * Female and male participants of childbearing potential who are sexually active must agree to use highly effective methods of contraception * Participants must have histologically confirmed locally advanced, recurrent, or metastatic solid tumor malignancies that cannot be treated with curative intent (surgery or radiotherapy), with the exception of the neoadjuvant cohorts * Part 1 and Part 2: Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 * Part 3 and Part 4: Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 * Participants who have undergone treatment with anti-PD-1, anti-PD-L1, or anti-cytotoxic T-lymphocyte-associated protein (CTLA-4) antibody must have a washout of at least 4 weeks from the last dose and evidence of disease progression per investigator assessment before Cycle 1 Day 1 (C1D1) with the exception of the neoadjuvant cohorts * Participants who have previously received an immunotherapy prior to C1D1 must have any immune-related toxicities resolved to ≤Grade 1 or baseline (prior to the immunotherapy) to be eligible, with the exception of participants on well controlled physiologic endocrine replacement * Part 3: Neoadjuvant cohorts: participants must have completely resectable disease Key
Exclusion criteria
* Symptomatic central nervous system metastases and/or carcinomatous meningitis * Active autoimmune diseases, regardless of need for immunosuppressive treatment, with the exception of participants well controlled on physiologic endocrine replacement * Any uncontrolled bacterial, fungal, viral, or other infection * Significant cardiac disease * A marked clinically significant baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval \>480 ms) \[CTCAE Grade 1\]) using Fridericia's QT correction formula * Positive for human immunodeficiency virus (HIV) or has known active hepatitis B or C infection * Known hypersensitivity to any study treatment(s) used in the specific study part/cohort * Participants who have been previously treated with IL-2 or IL-2 variants (all participants) * Systemic immunosuppressive treatment with the exception for patients on corticosteroid taper (for example, for chronic obstructive pulmonary disease exacerbation). * Vaccination with live, attenuated vaccines within 4 weeks of C1D1 * Treatment with any other anti-cancer systemic treatment (approved or investigational) or radiation therapy within 4 weeks of C1D1 * Part 3: Other active malignancies within the last 2 years * Women who are breastfeeding or have a positive serum pregnancy test during screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability | Through study completion, expected average of 2 years | Treatment emergent and treatment related adverse events (assessed by NCI CTCAE v5.0), serious adverse events (SAEs), adverse events leading to treatment discontinuation, deaths. |
| Maximum Tolerated Dose (MTD) | Each cycle is 21 days | Determine the maximum tolerated dose by assessing the Incidence of Dose Limiting Toxicities (DLTs), treatment emergent and treatment related adverse events (assessed by NCI CTCAE v5.0), serious adverse events (SAEs), adverse events leading to treatment discontinuation and deaths. |
| Recommended Phase 2 Dose (RP2D) | 12 months | To determine a recommended phase 2 dose of TransCon IL-2 β/γ and combination regimen for further development by evaluating number of patients with treatment-related adverse events as assessed by CTCAE. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Major Pathologic Response | 15 weeks | Evaluate the Major Pathologic Response (MPR) for anti-tumor activity of TransCon IL-2 β/γ alone or in combination with pembrolizumab, or TransCon TLR7/8 Agonist, or in combination with pembrolizumab and SOC chemotherapy in the Neoadjuvant Cohorts |
| Duration of Response | Average of 2 years | Time from first documentation of objective tumor response (CR or PR that is subsequently confirmed) to first documentation of disease progression or death due to any cause, whichever occurs first |
| Time to Response | Expected up to 1 year from first dose | Time from date of first dose of study treatment to first occurrence of response (CR or PR) |
| Progression Free Survival (PFS) | Average of 2 years | Time from date of first dose of study treatment to first documentation of disease progression or death due to any cause |
| Event free survival (EFS) by RECIST 1.1 | 2 years | Time from the date of the first dose of study treatment to the occurrence of any of the following: progression of disease that precludes surgery, disease recurrence after surgery, or death from any cause. |
| Overall Survival (OS) | Average of 2 years | Time from date of first dose of study treatment to date of death due to any cause |
| PK Characterization (Tmax) | Average of 2 years | Time to reach maximum plasma concentration of TransCon IL-2 β/γ and Free IL-2 β/γ after IV administration of TransCon IL-2 β/γ alone or in combination other therapies |
| PK Characterization (AUClast) | Average of 2 years | Area under the plasma concentration curve from time zero to last sampling time at which the concentration is at or above the lower limit of quantification for TransCon IL-2 β/γ and Free IL-2 β/γ after IV administration of TransCon IL-2 β/γ alone or in combination with other therapies |
| PK Characterization (AUC0-t) | Average of 2 years | Area under the plasma concentration curve from time zero to time t for TransCon IL-2 β/γ and Free IL-2 β/γ after IV administration of TransCon IL-2 β/γ alone or in combination with other therapies |
| PK Characterization (Cmax) | Average of 2 years | Maximum observed plasma concentration of TransCon IL-2 β/γ and Free IL-2 β/γ after IV administration of TransCon IL-2 β/γ alone or in combination with other therapies |
| PK Characterization (t1/2) | Average of 2 years | Apparent terminal half-life of TransCon IL-2 β/γ and Free IL-2 β/γ after IV administration of TransCon IL-2 β/γ alone or in combination with other therapies |
| Overall Response Rate | Average of 2 years | Response assessed by RECIST v1.1 |
| Pathologic Complete Response | 15 weeks | Evaluate the pathologic Complete Response (pCR) for anti-tumor activity of TransCon IL-2 β/γ alone or in combination with pembrolizumab, or TransCon TLR7/8 Agonist, or in combination with pembrolizumab and SOC chemotherapy in the Neoadjuvant Cohorts |
Countries
Australia, Belgium, Canada, Italy, Poland, Singapore, South Korea, Spain, Taiwan, United States
Contacts
STUDY_DIRECTORDavis Torrejon-Castro
Medical Monitor
Outcome results
None listed