A Study to Investigate Safety and Tolerability of TransCon IL-2 β/γ Alone or in Combination With Pembrolizumab and/or TransCon TLR7/8 Agonist or Other Anticancer Therapies in Adult Participants With Locally Advanced or Metastatic Solid Tumor Malignancies
- Conditions
- Advanced Solid TumorLocally Advanced Solid TumorMetastatic Solid TumorPlatinum-resistant Ovarian CancerPost Anti-PD-1 Melanoma2L+ Cervical CancerNeoadjuvant MelanomaNeoadjuvant Non-Small Cell Lung CancerPost Anti-PD-(L)1 Non-Small Cell Lung CancerPost Anti-PD-(L)1 Small Cell Lung Cancer
- Interventions
- Drug: TransCon IL-2 β/γDrug: Trastuzumab emtansine (T-DM1)Drug: TransCon TLR7/8 AgonistDrug: PembrolizumabDrug: TrastuzumabDrug: Chemotherapy drugProcedure: Surgery
- Registration Number
- NCT05081609
- Lead Sponsor
- Ascendis Pharma Oncology Division A/S
- 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 473
- 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
- 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
- Part 3, Post Anti-PD-1 Melanoma, 2L+ Cervical Cancer, and Neoadjuvant Melanoma: Participants who have been previously treated with IL-2 or IL-2 variants (all participants), or TLR agonist
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Part 3 Combination Dose Expansion:TransCon IL-2 β/γ + Pembrolizumab + SOC Chemo followed by surgery TransCon IL-2 β/γ TransCon IL-2 β/γ using the RP2D with Pembrolizumab and SOC Chemotherapy followed by surgery to evaluate safety/tolerability and anti-tumor activity of the combination Part 3 Combination Dose Expansion:TransCon IL-2 β/γ + Pembrolizumab + SOC Chemo followed by surgery Chemotherapy drug TransCon IL-2 β/γ using the RP2D with Pembrolizumab and SOC Chemotherapy followed by surgery to evaluate safety/tolerability and anti-tumor activity of the combination Part 3 Combination Dose Expansion:TransCon IL-2 β/γ + Pembrolizumab + SOC Chemo followed by surgery Surgery TransCon IL-2 β/γ using the RP2D with Pembrolizumab and SOC Chemotherapy followed by surgery to evaluate safety/tolerability and anti-tumor activity of the combination Part 3 Combination Dose Expansion TransCon IL-2 β/γ TransCon IL-2 β/γ + Pembrolizumab TransCon IL-2 β/γ using the RP2D with Pembrolizumab Part 3 Combination Dose Expansion: TransCon IL-2 β/γ monotherapy TransCon IL-2 β/γ TransCon IL-2 β/γ monotherapy Part 3 Combination Dose Expansion: TransCon IL-2 β/γ + trastuzumab TransCon IL-2 β/γ TransCon IL-2 β/γ + trastuzumab Part 3 Combination Dose Expansion: TransCon IL-2 β/γ + trastuzumab emtansine (T-DM1) TransCon IL-2 β/γ TransCon IL-2 β/γ + trastuzumab emtansine (T-DM1) Part 3 Combination Dose Expansion: TransCon IL-2 β/γ + trastuzumab emtansine (T-DM1) Trastuzumab emtansine (T-DM1) TransCon IL-2 β/γ + trastuzumab emtansine (T-DM1) Part 4 Combination Dose Optimization TransCon IL-2 β/γ TransCon IL-2 β/γ + Pembrolizumab TransCon IL-2 β/γ using the RP2D in titrating doses and/or different dose frequencies with Pembrolizumab Part 1 Monotherapy Dose Escalation: TransCon IL-2 β/γ TransCon IL-2 β/γ TransCon IL-2 β/γ in escalating doses to evaluate safety/tolerability and to determine the MTD and RP2D Part 2 Combination Dose Escalation: TransCon IL-2 β/γ with Pembrolizumab TransCon IL-2 β/γ TransCon IL-2 β/γ with Pembrolizumab in escalating doses to evaluate safety/tolerability and determine the MTD and RP2D Part 3 Combination Dose Expansion: TransCon IL-2 β/γ with SOC Chemo TransCon IL-2 β/γ TransCon IL-2 β/γ using the RP2D with SOC Chemotherapy to evaluate safety/tolerability and anti-tumor activity of the combination Part 3 Combination Dose Expansion: TransCon IL-2 β/γ with SOC Chemo Chemotherapy drug TransCon IL-2 β/γ using the RP2D with SOC Chemotherapy to evaluate safety/tolerability and anti-tumor activity of the combination Part 3 Combination Dose Expansion: TransCon IL-2 β/γ with TransCon TLR7/8 Agonist TransCon IL-2 β/γ TransCon IL-2 β/γ with TransCon TLR7/8 Agonist using the RP2D to evaluate safety/tolerability and anti-tumor activity of the combination Part 3 Combination Dose Expansion: TransCon IL-2 β/γ with TransCon TLR7/8 Agonist TransCon TLR7/8 Agonist TransCon IL-2 β/γ with TransCon TLR7/8 Agonist using the RP2D to evaluate safety/tolerability and anti-tumor activity of the combination Part 3 Monotherapy Dose Expansion: TransCon IL-2 β/γ followed by surgery TransCon IL-2 β/γ (Optional Arm): TransCon IL-2 β/γ using the RP2D followed by surgery to evaluate safety/tolerability and anti-tumor activity of the combination Part 3 Monotherapy Dose Expansion: TransCon IL-2 β/γ followed by surgery Surgery (Optional Arm): TransCon IL-2 β/γ using the RP2D followed by surgery to evaluate safety/tolerability and anti-tumor activity of the combination Part 3 Combination Dose Expansion: TransCon IL-2 β/γ with Pembrolizumab followed by surgery TransCon IL-2 β/γ TransCon IL-2 β/γ using the RP2D with Pembrolizumab followed by surgery to evaluate safety/tolerability and anti-tumor activity of the combination Part 3 Combination Dose Expansion: TransCon IL-2 β/γ with Pembrolizumab followed by surgery Pembrolizumab TransCon IL-2 β/γ using the RP2D with Pembrolizumab followed by surgery to evaluate safety/tolerability and anti-tumor activity of the combination Part 3 Combination Dose Expansion: TransCon IL-2 β/γ with Pembrolizumab followed by surgery Surgery TransCon IL-2 β/γ using the RP2D with Pembrolizumab followed by surgery to evaluate safety/tolerability and anti-tumor activity of the combination Part 3 Combination Dose Expansion:TransCon IL-2 β/γ with TransCon TLR7/8 Agonist followed by surgery TransCon IL-2 β/γ TransCon IL-2 β/γ with TransCon TLR7/8 Agonist using the RP2D followed by surgery to evaluate safety/tolerability and anti-tumor activity of the combination Part 3 Combination Dose Expansion:TransCon IL-2 β/γ with TransCon TLR7/8 Agonist followed by surgery TransCon TLR7/8 Agonist TransCon IL-2 β/γ with TransCon TLR7/8 Agonist using the RP2D followed by surgery to evaluate safety/tolerability and anti-tumor activity of the combination Part 3 Combination Dose Expansion:TransCon IL-2 β/γ with TransCon TLR7/8 Agonist followed by surgery Surgery TransCon IL-2 β/γ with TransCon TLR7/8 Agonist using the RP2D followed by surgery to evaluate safety/tolerability and anti-tumor activity of the combination Part 2 Combination Dose Escalation: TransCon IL-2 β/γ with Pembrolizumab Pembrolizumab TransCon IL-2 β/γ with Pembrolizumab in escalating doses to evaluate safety/tolerability and determine the MTD and RP2D Part 3 Combination Dose Expansion Pembrolizumab TransCon IL-2 β/γ + Pembrolizumab TransCon IL-2 β/γ using the RP2D with Pembrolizumab Part 4 Combination Dose Optimization Pembrolizumab TransCon IL-2 β/γ + Pembrolizumab TransCon IL-2 β/γ using the RP2D in titrating doses and/or different dose frequencies with Pembrolizumab Part 3 Combination Dose Expansion:TransCon IL-2 β/γ + Pembrolizumab + SOC Chemo followed by surgery Pembrolizumab TransCon IL-2 β/γ using the RP2D with Pembrolizumab and SOC Chemotherapy followed by surgery to evaluate safety/tolerability and anti-tumor activity of the combination Part 3 Combination Dose Expansion: TransCon IL-2 β/γ + trastuzumab Trastuzumab TransCon IL-2 β/γ + trastuzumab
- Primary Outcome Measures
Name Time Method 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 Outcome Measures
Name Time Method 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
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 (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 (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 (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
Trial Locations
- Locations (1)
Ascendis Pharma Investigational Site
🇨🇳Taipei, Taiwan