A Study to Investigate Safety and Tolerability of TransCon IL-2 β/γ Alone or in Combination With Pembrolizumab and/or Chemotherapy or TransCon TLR7/8 Agonist in Adult Participants With Locally Advanced or Metastatic Solid Tumor Malignancies

Study Overview
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Brief Summary
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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
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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.

Official Title
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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, Standard of Care Chemotherapy, or TransCon TLR7/8 Agonist, or in Combination With Pembrolizumab and Standard of Care Chemotherapy, in Adult Participants With Locally Advanced or Metastatic Solid Tumor Malignancies

Conditions
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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

Intervention / Treatment
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* Drug: TransCon IL-2 β/γ
* Drug: Pembrolizumab
* Drug: Chemotherapy drug
* Drug: TransCon TLR7/8 Agonist
* Procedure: Surgery


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: At least 18 years of age Demonstrated adequate organ function at screening Life expectancy >12 weeks as determined by the Investigator At least 1 lesion of measurable disease, except for Post Anti-PD-1 Melanoma and 2L+ Cervical Cancer (at least 2 lesions of measurable disease) 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: Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 Part 1 and Part 2: Participants who have undergone treatment with anti-PD-1, anti-PD-L1, or anti-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) Part 1 and Part 2: 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: Part 3, neoadjuvant cohorts: participants must have completely resectable disease Key Exclusion Criteria: Symptomatic central nervous system metastases 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 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), or TLR agonist (Part 3 only for Post Anti-PD-1 Melanoma, 2L+ Cervical Cancer, and Neoadjuvant Melanoma) 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 Monotherapy Dose Escalation: TransCon IL-2 β/γ<br>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<br>* TransCon IL-2 β/γ will be administered as an intravenous (IV) infusion<br>|
| Experimental: Part 2 Combination Dose Escalation: TransCon IL-2 β/γ with Pembrolizumab<br>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<br>* TransCon IL-2 β/γ will be administered as an intravenous (IV) infusion<br>Drug: Pembrolizumab<br>* Pembrolizumab will be administered as an intravenous (IV) infusion<br>|
| Experimental: Part 3 Combination Dose Expansion: TransCon IL-2 β/γ with SOC Chemo<br>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<br>* TransCon IL-2 β/γ will be administered as an intravenous (IV) infusion<br>Drug: Chemotherapy drug<br>* SOC chemotherapy will be administered as an intravenous (IV) infusion<br>|
| Experimental: Part 3 Combination Dose Expansion: TransCon IL-2 β/γ with TransCon TLR7/8 Agonist<br>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<br>* TransCon IL-2 β/γ will be administered as an intravenous (IV) infusion<br>Drug: TransCon TLR7/8 Agonist<br>* TransCon TLR7/8 Agonist will be administered as an IT (Intratumoral) injection<br>|
| Experimental: Part 3 Monotherapy Dose Expansion: TransCon IL-2 β/γ followed by surgery<br>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<br>* TransCon IL-2 β/γ will be administered as an intravenous (IV) infusion<br>Procedure: Surgery<br>* Surgery will take place 4-6 weeks after last dose of study treatment.<br>|
| Experimental: Part 3 Combination Dose Expansion: TransCon IL-2 β/γ with Pembrolizumab followed by surgery<br>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<br>* TransCon IL-2 β/γ will be administered as an intravenous (IV) infusion<br>Drug: Pembrolizumab<br>* Pembrolizumab will be administered as an intravenous (IV) infusion<br>Procedure: Surgery<br>* Surgery will take place 4-6 weeks after last dose of study treatment.<br>|
| Experimental: Part 3 Combination Dose Expansion:TransCon IL-2 β/γ with TransCon TLR7/8 Agonist followed by surgery<br>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<br>* TransCon IL-2 β/γ will be administered as an intravenous (IV) infusion<br>Drug: TransCon TLR7/8 Agonist<br>* TransCon TLR7/8 Agonist will be administered as an IT (Intratumoral) injection<br>Procedure: Surgery<br>* Surgery will take place 4-6 weeks after last dose of study treatment.<br>|
| Experimental: Part 3 Combination Dose Expansion:TransCon IL-2 β/γ + Pembrolizumab + SOC Chemo followed by surgery<br>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<br>* TransCon IL-2 β/γ will be administered as an intravenous (IV) infusion<br>Drug: Pembrolizumab<br>* Pembrolizumab will be administered as an intravenous (IV) infusion<br>Drug: Chemotherapy drug<br>* SOC chemotherapy will be administered as an intravenous (IV) infusion<br>Procedure: Surgery<br>* Surgery will take place 4-6 weeks after last dose of study treatment.<br>|

What is the study measuring?
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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 |