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)

Ascendis Pharma

Status and phase: Enrolling; Phase 2; Phase 1

Conditions: Post Anti-PD-1 Melanoma; Second or Third Line (2L/3L) Cervical Cancer; Post Anti-PD-(L)1 Small Cell Lung Cancer; Locally Advanced Solid Tumor; Neoadjuvant Non-Small Cell Lung Cancer; Advanced Solid Tumor; Platinum-resistant Ovarian Cancer; Neoadjuvant Melanoma; Third Line or Later (3L+) HER2+ Breast Cancer; 2L+ Cervical Cancer; Metastatic Solid Tumor; Post Anti-PD-(L)1 Non-Small Cell Lung Cancer

Treatments: Drug: TransCon TLR7/8 Agonist; Drug: Trastuzumab emtansine (T-DM1); Drug: Pembrolizumab; Drug: Trastuzumab; Drug: TransCon IL-2 β/γ; Procedure: Surgery; Drug: Chemotherapy drug

Study type: Interventional

Funder types: Industry

Identifiers

NCT05081609

ASND0029

Details and patient eligibility

About

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.

Full 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.

Enrollment: 473 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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
• 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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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473 participants in 13 patient groups

Part 1 Monotherapy Dose Escalation: TransCon IL-2 β/γ

Experimental group

Description:

TransCon IL-2 β/γ in escalating doses to evaluate safety/tolerability and to determine the MTD and RP2D

Treatment:

Drug: TransCon IL-2 β/γ

Part 2 Combination Dose Escalation: TransCon IL-2 β/γ with Pembrolizumab

Experimental group

Description:

TransCon IL-2 β/γ with Pembrolizumab in escalating doses to evaluate safety/tolerability and determine the MTD and RP2D

Treatment:

Drug: TransCon IL-2 β/γ

Drug: Pembrolizumab

Part 3 Combination Dose Expansion: TransCon IL-2 β/γ with SOC Chemo

Experimental group

Description:

TransCon IL-2 β/γ using the RP2D with SOC Chemotherapy to evaluate safety/tolerability and anti-tumor activity of the combination

Treatment:

Drug: Chemotherapy drug

Drug: TransCon IL-2 β/γ

Part 3 Combination Dose Expansion: TransCon IL-2 β/γ with TransCon TLR7/8 Agonist

Experimental group

Description:

TransCon IL-2 β/γ with TransCon TLR7/8 Agonist using the RP2D to evaluate safety/tolerability and anti-tumor activity of the combination

Treatment:

Drug: TransCon IL-2 β/γ

Drug: TransCon TLR7/8 Agonist

Part 3 Monotherapy Dose Expansion: TransCon IL-2 β/γ followed by surgery

Experimental group

Description:

(Optional Arm): TransCon IL-2 β/γ using the RP2D followed by surgery to evaluate safety/tolerability and anti-tumor activity of the combination

Treatment:

Procedure: Surgery

Drug: TransCon IL-2 β/γ

Part 3 Combination Dose Expansion: TransCon IL-2 β/γ with Pembrolizumab followed by surgery

Experimental group

Description:

TransCon IL-2 β/γ using the RP2D with Pembrolizumab followed by surgery to evaluate safety/tolerability and anti-tumor activity of the combination

Treatment:

Procedure: Surgery

Drug: TransCon IL-2 β/γ

Drug: Pembrolizumab

Part 3 Combination Dose Expansion:TransCon IL-2 β/γ with TransCon TLR7/8 Agonist followed by surgery

Experimental group

Description:

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

Treatment:

Procedure: Surgery

Drug: TransCon IL-2 β/γ

Drug: TransCon TLR7/8 Agonist

Part 3 Combination Dose Expansion:TransCon IL-2 β/γ + Pembrolizumab + SOC Chemo followed by surgery

Experimental group

Description:

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

Treatment:

Drug: Chemotherapy drug

Procedure: Surgery

Drug: TransCon IL-2 β/γ

Drug: Pembrolizumab

Part 3 Combination Dose Expansion

Experimental group

Description:

TransCon IL-2 β/γ + Pembrolizumab TransCon IL-2 β/γ using the RP2D with Pembrolizumab

Treatment:

Drug: TransCon IL-2 β/γ

Drug: Pembrolizumab

Part 3 Combination Dose Expansion: TransCon IL-2 β/γ monotherapy

Experimental group

Description:

TransCon IL-2 β/γ monotherapy

Treatment:

Drug: TransCon IL-2 β/γ

Part 3 Combination Dose Expansion: TransCon IL-2 β/γ + trastuzumab

Experimental group

Description:

TransCon IL-2 β/γ + trastuzumab

Treatment:

Drug: TransCon IL-2 β/γ

Drug: Trastuzumab

Part 3 Combination Dose Expansion: TransCon IL-2 β/γ + trastuzumab emtansine (T-DM1)

Experimental group

Description:

TransCon IL-2 β/γ + trastuzumab emtansine (T-DM1)

Treatment:

Drug: TransCon IL-2 β/γ

Drug: Trastuzumab emtansine (T-DM1)

Part 4 Combination Dose Optimization

Experimental group

Description:

TransCon IL-2 β/γ + Pembrolizumab TransCon IL-2 β/γ using the RP2D in titrating doses and/or different dose frequencies with Pembrolizumab

Treatment:

Drug: TransCon IL-2 β/γ

Drug: Pembrolizumab