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 (IL Believe)

IL Believe: A Phase 1/2, Open-label, Dose Escalation and Dose Expansion Study to Investigate 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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Advanced Solid Tumor; Metastatic Solid Tumor; Platinum-resistant Ovarian Cancer; Locally Advanced Solid Tumor; 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)
• Intervention / Treatment: Drug: TransCon IL-2 β/γ; Drug: Pembrolizumab; Drug: Chemotherapy drug; Drug: TransCon TLR7/8 Agonist; Procedure: Surgery; Drug: Trastuzumab; Drug: Trastuzumab emtansine (T-DM1)

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.

• Study Type: Interventional
• Enrollment (Actual): 320
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Australia
  • Adelaide, Australia, 5000
    • Ascendis Pharma Investigational Site
  • Adelaide, Australia, 5042
    • Ascendis Pharma Investigational Site
  • Brisbane, Australia, 04120
    • Ascendis Pharma Investigational Site
  • Frankston, Australia, 3199
    • Ascendis Pharma Investigational Site
  • Southport, Australia, 4215
    • Ascendis Pharma Investigational Site
  • Toorak Gardens, Australia, 05065
    • Ascendis Pharma Investigational Site
  • Waratah, Australia, 2298
    • Ascendis Pharma Investigational Site
• Belgium
  • Wilrijk, Belgium, 2610
    • Ascendis Pharma Investigational Site
• Canada
  • Montreal, Canada, H4A 3J1
    • Ascendis Pharma Investigational Site
  • Toronto, Canada, M4N 3M5
    • Ascendis Pharma Investigational Site
  • Toronto, Canada, M5G 2C4
    • Ascendis Pharma Investigational Site
• Italy
  • Cuneo, Italy, 12100
    • Ascendis Pharma Investigational Site
  • Florence, Italy, 50134
    • Ascendis Pharma Investigational Site
  • Grosseto, Italy, 58100
    • Ascendis Pharma Investigational Site
  • Lido di Camaiore, Italy, 55041
    • Ascendis Pharma Investigational Site
  • Livorno, Italy, 57124
    • Ascendis Pharma Investigational Site
  • Meldola, Italy, 47014
    • Ascendis Pharma Investigational Site
  • Milan, Italy, 20133
    • Ascendis Pharma Investigational Site
  • Milan, Italy, 20141
    • Ascendis Pharma Investigational Site
  • Modena, Italy, 41124
    • Ascendis Pharma Investigational Site
  • Roma, Italy, 00167
    • Ascendis Pharma Investigational Site
  • Torino, Italy, 10126
    • Ascendis Pharma Investigational Site
  • Turin, Italy, 10060
    • Ascendis Pharma Investigational Site
  • Verona, Italy, 37134
    • Ascendis Pharma Investigational Site
• Poland
  • Krakow, Poland, 31-501
    • Ascendis Pharma Investigational Site
  • Poznan, Poland, 60693
    • Ascendis Pharma Investigational Site
  • Warsaw, Poland, 02-781
    • Ascendis Pharma Investigational Site
• Singapore
  • Singapore, Singapore, 119228
    • Ascendis Pharma Investigational Site
  • Singapore, Singapore, 217562
    • Ascendis Pharma Investigational Site
• South Korea
  • Seongnam-si, South Korea, 13620
    • Ascendis Pharma Investigational Site
  • Seoul, South Korea, 03080
    • Ascendis Pharma Investigational Site
  • Seoul, South Korea, 03722
    • Ascendis Pharma Investigational Site
  • Seoul, South Korea, 06231
    • Ascendis Pharma Investigational Site
  • Seoul, South Korea, 06351
    • Ascendis Pharma Investigational Site
  • Songpa-gu
    • Seoul, Songpa-gu, South Korea, 05505
      • Ascendis Pharma Investigational Site
• Spain
  • Barcelona, Spain, 08035
    • Ascendis Pharma Investigational Site
  • Barcelona, Spain, 08023
    • Ascendis Pharma Investigational Site
  • Barcelona, Spain, 08028
    • Ascendis Pharma Investigational Site
  • L'Hospitalet de Llobregat, Spain, 08908
    • Ascendis Pharma Investigational Site
  • Madrid, Spain, 28006
    • Ascendis Pharma Investigational Site
  • Madrid, Spain, 28027
    • Ascendis Pharma Investigational Site
  • Madrid, Spain, 28040
    • Ascendis Pharma Investigational Site
  • Madrid, Spain, 28041
    • Ascendis Pharma Investigational Site
  • Madrid, Spain, 28050
    • Ascendis Pharma Investigational Site
  • Murcia, Spain, 30120
    • Ascendis Pharma Investigational Site
  • Málaga, Spain, 29010
    • Ascendis Pharma Investigational Site
  • Oviedo, Spain, 33011
    • Ascendis Pharma Investigational Site
  • Pamplona, Spain, 31008
    • Ascendis Pharma Investigational Site
  • Seville, Spain, 41009
    • Ascendis Pharma Investigational Site
  • Seville, Spain, 41014
    • Ascendis Pharma Investigational Site
  • Valencia, Spain, 46009
    • Ascendis Pharma Investigational Site
  • Valencia, Spain, 46014
    • Ascendis Pharma Investigational Site
• Taiwan
  • Taipei, Taiwan, 10002
    • Ascendis Pharma Investigational Site
  • Taipei, Taiwan, 11259
    • Ascendis Pharma Investigational Site
• United States
  • California
    • Los Angeles, California, United States, 90048
      • Ascendis Pharma Investigational Site
    • Los Angeles, California, United States, 90067
      • Ascendis Pharma Investigational Site
  • Illinois
    • Springfield, Illinois, United States, 62702
      • Ascendis Pharma Investigational Site
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Ascendis Pharma Investigational Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Ascendis Pharma Investigational Site
  • New Jersey
    • Morristown, New Jersey, United States, 07960
      • Ascendis Pharma Investigational Site
  • New York
    • New York, New York, United States, 10032
      • Ascendis Pharma Investigational Site
  • North Carolina
    • Huntersville, North Carolina, United States, 28078
      • Ascendis Pharma Investigational Site
  • Ohio
    • Canton, Ohio, United States, 44718
      • Ascendis Pharma Investigational Site
    • Cincinnati, Ohio, United States, 45219
      • Ascendis Pharma Investigational Site
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Ascendis Pharma Investigational Site
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • Ascendis Pharma Investigational Site
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Ascendis Pharma Investigational Site
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Ascendis Pharma Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

13

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1 Monotherapy Dose Escalation: TransCon IL-2 β/γ; TransCon IL-2 β/γ in escalating doses to evaluate safety/tolerability and to determine the MTD and RP2D	Drug: TransCon IL-2 β/γ; TransCon IL-2 β/γ will be administered as an intravenous (IV) infusion
Experimental: Part 2 Combination Dose Escalation: TransCon IL-2 β/γ with Pembrolizumab; TransCon IL-2 β/γ with Pembrolizumab in escalating doses to evaluate safety/tolerability and determine the MTD and RP2D	Drug: TransCon IL-2 β/γ; TransCon IL-2 β/γ will be administered as an intravenous (IV) infusion; Drug: Pembrolizumab; Pembrolizumab will be administered as an intravenous (IV) infusion
Experimental: Part 3 Combination Dose Expansion: TransCon IL-2 β/γ with SOC Chemo; TransCon IL-2 β/γ using the RP2D with SOC Chemotherapy to evaluate safety/tolerability and anti-tumor activity of the combination	Drug: TransCon IL-2 β/γ; TransCon IL-2 β/γ will be administered as an intravenous (IV) infusion; Drug: Chemotherapy drug; SOC chemotherapy will be administered as an intravenous (IV) infusion
Experimental: Part 3 Combination Dose Expansion: TransCon IL-2 β/γ with 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	Drug: TransCon IL-2 β/γ; TransCon IL-2 β/γ will be administered as an intravenous (IV) infusion; Drug: TransCon TLR7/8 Agonist; TransCon TLR7/8 Agonist will be administered as an IT (Intratumoral) injection
Experimental: Part 3 Combination Dose Expansion: TransCon IL-2 β/γ with Pembrolizumab followed by 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	Drug: TransCon IL-2 β/γ; TransCon IL-2 β/γ will be administered as an intravenous (IV) infusion; Drug: Pembrolizumab; Pembrolizumab will be administered as an intravenous (IV) infusion; Procedure: Surgery; Surgery will take place 4-6 weeks after last dose of study treatment.
Experimental: Part 3 Combination Dose Expansion:TransCon IL-2 β/γ with TransCon TLR7/8 Agonist followed by 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	Drug: TransCon IL-2 β/γ; TransCon IL-2 β/γ will be administered as an intravenous (IV) infusion; Drug: TransCon TLR7/8 Agonist; TransCon TLR7/8 Agonist will be administered as an IT (Intratumoral) injection; Procedure: Surgery; Surgery will take place 4-6 weeks after last dose of study treatment.
Experimental: Part 3 Combination Dose Expansion:TransCon IL-2 β/γ + Pembrolizumab + SOC Chemo followed by 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	Drug: TransCon IL-2 β/γ; TransCon IL-2 β/γ will be administered as an intravenous (IV) infusion; Drug: Pembrolizumab; Pembrolizumab will be administered as an intravenous (IV) infusion; Drug: Chemotherapy drug; SOC chemotherapy will be administered as an intravenous (IV) infusion; Procedure: Surgery; Surgery will take place 4-6 weeks after last dose of study treatment.
Experimental: Part 3 Monotherapy Dose Expansion: TransCon IL-2 β/γ followed by 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	Drug: TransCon IL-2 β/γ; TransCon IL-2 β/γ will be administered as an intravenous (IV) infusion; Procedure: Surgery; Surgery will take place 4-6 weeks after last dose of study treatment.
Experimental: Part 3 Combination Dose Expansion; TransCon IL-2 β/γ + Pembrolizumab TransCon IL-2 β/γ using the RP2D with Pembrolizumab	Drug: TransCon IL-2 β/γ; TransCon IL-2 β/γ will be administered as an intravenous (IV) infusion; Drug: Pembrolizumab; Pembrolizumab will be administered as an intravenous (IV) infusion
Experimental: Part 4 Combination Dose Optimization; TransCon IL-2 β/γ + Pembrolizumab TransCon IL-2 β/γ using the RP2D in titrating doses and/or different dose frequencies with Pembrolizumab	Drug: TransCon IL-2 β/γ; TransCon IL-2 β/γ will be administered as an intravenous (IV) infusion; Drug: Pembrolizumab; Pembrolizumab will be administered as an intravenous (IV) infusion
Experimental: Part 3 Combination Dose Expansion: TransCon IL-2 β/γ monotherapy; TransCon IL-2 β/γ monotherapy	Drug: TransCon IL-2 β/γ; TransCon IL-2 β/γ will be administered as an intravenous (IV) infusion
Experimental: Part 3 Combination Dose Expansion: TransCon IL-2 β/γ + trastuzumab; TransCon IL-2 β/γ + trastuzumab	Drug: TransCon IL-2 β/γ; TransCon IL-2 β/γ will be administered as an intravenous (IV) infusion; Drug: Trastuzumab; Trastuzumab will be administered as an intravenous (IV) infusion
Experimental: Part 3 Combination Dose Expansion: TransCon IL-2 β/γ + trastuzumab emtansine (T-DM1); TransCon IL-2 β/γ + trastuzumab emtansine (T-DM1)	Drug: TransCon IL-2 β/γ; TransCon IL-2 β/γ will be administered as an intravenous (IV) infusion; Drug: Trastuzumab emtansine (T-DM1); Trastuzumab emtansine (T-DM1) will be administered as an intravenous (IV) infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and Tolerability	Treatment emergent and treatment related adverse events (assessed by NCI CTCAE v5.0), serious adverse events (SAEs), adverse events leading to treatment discontinuation, deaths.	Through study completion, expected average of 2 years
Maximum Tolerated Dose (MTD)	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.	Each cycle is 21 days
Recommended Phase 2 Dose (RP2D)	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.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate	Response assessed by RECIST v1.1	Average of 2 years
Pathologic Complete Response	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	15 weeks
Major Pathologic Response	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	15 weeks
Duration of Response	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	Average of 2 years
Time to Response	Time from date of first dose of study treatment to first occurrence of response (CR or PR)	Expected up to 1 year from first dose
Progression Free Survival (PFS)	Time from date of first dose of study treatment to first documentation of disease progression or death due to any cause	Average of 2 years
Event free survival (EFS) by RECIST 1.1	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.	2 years
Overall Survival (OS)	Time from date of first dose of study treatment to date of death due to any cause	Average of 2 years
PK Characterization (Cmax)	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	Average of 2 years
PK Characterization (Tmax)	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	Average of 2 years
PK Characterization (AUClast)	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	Average of 2 years
PK Characterization (AUC0-t)	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	Average of 2 years
PK Characterization (t1/2)	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	Average of 2 years

Collaborators and Investigators

• Sponsor: Ascendis Pharma Oncology Division A/S
• Investigators: Study Director: Davis Torrejon-Castro, Medical Monitor

Publications and helpful links

General Publications

• Rosen DB, Kvarnhammar AM, Laufer B, Knappe T, Karlsson JJ, Hong E, Lee YC, Thakar D, Zuniga LA, Bang K, Sabharwal SS, Uppal K, Olling JD, Kjaergaard K, Kurpiers T, Schnabel M, Reich D, Glock P, Zettler J, Krusch M, Bernhard A, Heinig S, Konjik V, Wegge T, Hehn Y, Killian S, Viet L, Runz J, Faltinger F, Tabrizi M, Abel KL, Breinholt VM, Singel SM, Sprogoe K, Punnonen J. TransCon IL-2 beta/gamma: a novel long-acting prodrug with sustained release of an IL-2Rbeta/gamma-selective IL-2 variant with improved pharmacokinetics and potent activation of cytotoxic immune cells for the treatment of cancer. J Immunother Cancer. 2022 Jul;10(7):e004991. doi: 10.1136/jitc-2022-004991.

Study record dates

Study Major Dates

• Study Start (Actual): January 11, 2022
• Primary Completion (Estimated): August 1, 2027
• Study Completion (Estimated): August 1, 2029

Study Registration Dates

• First Submitted: October 5, 2021
• First Submitted That Met QC Criteria: October 5, 2021
• First Posted (Actual): October 18, 2021

Study Record Updates

• Last Update Posted (Actual): February 24, 2026
• Last Update Submitted That Met QC Criteria: February 23, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Pathologic Processes; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Uterine Diseases; Genital Diseases, Female; Neoplastic Processes; Genital Neoplasms, Female; Uterine Cervical Diseases; Uterine Neoplasms; Pathological Conditions, Signs and Symptoms; Neoplasm Metastasis; Uterine Cervical Neoplasms; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Polycyclic Compounds; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Macrolides; Lactones; Lactams, Macrocyclic; Macrocyclic Compounds; Maytansine; Trastuzumab; Ado-Trastuzumab Emtansine; pembrolizumab; Surgical Procedures, Operative
• Other Study ID Numbers: ASND0029

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No