Clinical trial NCT05081609: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: 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)
Lead sponsor: Ascendis Pharma A/S
Sponsor class: INDUSTRY
First posted: 2021-10-18
Enrollment: 345
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: Safety and Tolerability
timeFrame: Through study completion, expected average of 2 years
measure: Maximum Tolerated Dose (MTD)
timeFrame: Each cycle is 21 days
measure: Recommended Phase 2 Dose (RP2D)
timeFrame: 12 months
Secondary outcomes:
measure: Overall Response Rate
timeFrame: Average of 2 years
measure: Pathologic Complete Response
timeFrame: 15 weeks
measure: Major Pathologic Response
timeFrame: 15 weeks
measure: Duration of Response
timeFrame: Average of 2 years
measure: Time to Response
timeFrame: Expected up to 1 year from first dose
measure: Progression Free Survival (PFS)
timeFrame: Average of 2 years
measure: Event free survival (EFS) by RECIST 1.1
timeFrame: 2 years
measure: Overall Survival (OS)
timeFrame: Average of 2 years
measure: PK Characterization (Cmax)
timeFrame: Average of 2 years
measure: PK Characterization (Tmax)
timeFrame: Average of 2 years
measure: PK Characterization (AUClast)
timeFrame: Average of 2 years
measure: PK Characterization (AUC0-t)
timeFrame: Average of 2 years
measure: PK Characterization (t1/2)
timeFrame: Average of 2 years
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Ascendis Pharma Investigational Site
state: California
city: Los Angeles
country: United States
facility: Ascendis Pharma Investigational Site
state: California
city: Springfield
country: United States
facility: Ascendis Pharma Investigational Site
state: Illinois
city: Louisville
country: United States
facility: Ascendis Pharma Investigational Site
state: Kentucky
city: Boston
country: United States
facility: Ascendis Pharma Investigational Site
state: Massachusetts
city: Morristown
country: United States
facility: Ascendis Pharma Investigational Site
state: New Jersey
city: New York
country: United States
facility: Ascendis Pharma Investigational Site
state: New York
city: Huntersville
country: United States
facility: Ascendis Pharma Investigational Site
state: North Carolina
city: Canton
country: United States
facility: Ascendis Pharma Investigational Site
state: Ohio
city: Cincinnati
country: United States
facility: Ascendis Pharma Investigational Site
state: Ohio
city: Oklahoma City
country: United States
facility: Ascendis Pharma Investigational Site
state: Oklahoma
city: Pittsburgh
country: United States
facility: Ascendis Pharma Investigational Site
state: Pennsylvania
city: Nashville
country: United States
facility: Ascendis Pharma Investigational Site
state: Tennessee
city: Richmond
country: United States
facility: Ascendis Pharma Investigational Site
state: Virginia
city: Adelaide
country: Australia
facility: Ascendis Pharma Investigational Site
city: Adelaide
country: Australia
facility: Ascendis Pharma Investigational Site
city: Frankston
country: Australia
facility: Ascendis Pharma Investigational Site
city: Southport
country: Australia
facility: Ascendis Pharma Investigational Site
city: Toorak Gardens
country: Australia
facility: Ascendis Pharma Investigational Site
city: Waratah
country: Australia
facility: Ascendis Pharma Investigational Site
city: Wilrijk
country: Belgium
facility: Ascendis Pharma Investigational Site
city: Montréal
country: Canada
facility: Ascendis Pharma Investigational Site
city: Montréal
country: Canada
facility: Ascendis Pharma Investigational Site
city: Toronto
country: Canada
facility: Ascendis Pharma Investigational Site
city: Toronto
country: Canada
facility: Ascendis Pharma Investigational Site
city: Cuneo
country: Italy
facility: Ascendis Pharma Investigational Site
city: Firenze
country: Italy
facility: Ascendis Pharma Investigational Site
city: Grosseto
country: Italy
facility: Ascendis Pharma Investigational Site
city: Lido Di Camaiore
country: Italy
facility: Ascendis Pharma Investigational Site
city: Livorno
country: Italy
facility: Ascendis Pharma Investigational Site
city: Meldola
country: Italy
facility: Ascendis Pharma Investigational Site
city: Milan
country: Italy
facility: Ascendis Pharma Investigational Site
city: Milan
country: Italy
facility: Ascendis Pharma Investigational Site
city: Modena
country: Italy
facility: Ascendis Pharma Investigational Site
city: Roma
country: Italy
facility: Ascendis Pharma Investigational Site
city: Torino
country: Italy
facility: Ascendis Pharma Investigational Site
city: Turin
country: Italy
facility: Ascendis Pharma Investigational Site
city: Verona
country: Italy
facility: Ascendis Pharma Investigational Site
city: Seoul
country: Korea, Republic of
facility: Ascendis Pharma Investigational Site
state: Songpa-gu
city: Seongnam-si
country: Korea, Republic of
facility: Ascendis Pharma Investigational Site
city: Seoul
country: Korea, Republic of
facility: Ascendis Pharma Investigational Site
city: Seoul
country: Korea, Republic of
facility: Ascendis Pharma Investigational Site
city: Seoul
country: Korea, Republic of
facility: Ascendis Pharma Investigational Site
city: Seoul
country: Korea, Republic of
facility: Ascendis Pharma Investigational Site
city: Kraków
country: Poland
facility: Ascendis Pharma Investigational Site
city: Poznań
country: Poland
facility: Ascendis Pharma Investigational Site
city: Warszawa
country: Poland
facility: Ascendis Pharma Investigational Site
city: Singapore
country: Singapore
facility: Ascendis Pharma Investigational Site
city: Singapore
country: Singapore
facility: Ascendis Pharma Investigational Site
city: Barcelona
country: Spain
facility: Ascendis Pharma Investigational Site
city: Barcelona
country: Spain
facility: Ascendis Pharma Investigational Site
city: L'Hospitalet De Llobregat
country: Spain
facility: Ascendis Pharma Investigational Site
city: Madrid
country: Spain
facility: Ascendis Pharma Investigational Site
city: Madrid
country: Spain
facility: Ascendis Pharma Investigational Site
city: Madrid
country: Spain
facility: Ascendis Pharma Investigational Site
city: Madrid
country: Spain
facility: Ascendis Pharma Investigational Site
city: Madrid
country: Spain
facility: Ascendis Pharma Investigational Site
city: Murcia
country: Spain
facility: Ascendis Pharma Investigational Site
city: Málaga
country: Spain
facility: Ascendis Pharma Investigational Site
city: Oviedo
country: Spain
facility: Ascendis Pharma Investigational Site
city: Pamplona
country: Spain
facility: Ascendis Pharma Investigational Site
city: Sevilla
country: Spain
facility: Ascendis Pharma Investigational Site
city: Sevilla
country: Spain
facility: Ascendis Pharma Investigational Site
city: Valencia
country: Spain
facility: Ascendis Pharma Investigational Site
city: Valencia
country: Spain
facility: Ascendis Pharma Investigational Site
city: Taipei
country: Taiwan
facility: Ascendis Pharma Investigational Site
city: Taipei
country: Taiwan
facility: Ascendis Pharma Investigational Site
Study officials:
affiliation: Medical Monitor
name: Davis Torrejon-Castro
role: STUDY_DIRECTOR
References:
citation: 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.