A Study to Investigate 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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Ascendis Pharma Oncology Division A/S

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

27 Nov 2023 → ongoing

Decision date (initial)

2023-12-15

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2023-509143-27-00

EudraCT number

2022-001191-34

ClinicalTrials.gov

NCT05081609

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety

The main objective of Part 1 and 2 was to evaluate the safety and tolerability, and define the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of TransCon IL-2 β/γ alone or in combination with pembrolizumab.

The main objective of Part 3 and Part 4 is to evaluate the safety and tolerability of TransCon IL-2 β/γ at RP2D as monotherapy and in combination with pembrolizumab, standard of care (SOC) chemotherapy, or TransCon TLR7/8 Agonist, or in combination with pembrolizumab and SOC chemotherapy or in combination with SOC trastuzumab or SOC trastuzumab emtansine (T-DM1)

Secondary objectives 2

1. To evaluate the antitumor activity of 1) TransCon IL-2 β/γ alone, or 2) in combination with pembrolizumab, SOC chemotherapy, or TransCon TLR7/8 Agonist, or 3) in combination with pembrolizumab and SOC chemotherapy, or 4) in combination with SOC trastuzumab or SOC trastuzumab emtansine (T-DM1)
2. To characterize the plasma pharmacokinetics (PK) of TransCon IL-2 β/γ and Free IL-2 β/γ alone or in combination with pembrolizumab, SOC chemotherapy, or TransCon TLR7/8 Agonist, or in combination with pembrolizumab and SOC chemotherapy, or in combination with SOC trastuzumab or SOC trastuzumab emtansine (T-DM1)

Conditions and MedDRA coding

Locally advanced or metastatic solid tumor malignancies, platinum resistant ovarian cancer, post-anti-pd-1 melanoma, second line or later cervical cancer, neoadjuvant melanoma and neoadjuvant non-small cell lung cancer, post-anti-pd-L1 non-small cell lung cancer, post-anti-pd-L1 small cell lung cancer, second line or later HER2+ breast cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 16

1. • At least 18 years of age or country defined local legal age • Adequate organ function at screening Part 1 and Part 2: Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 Part 3 or Part 4 : ECOG performance status of 0 or 1
2. Neoadjuvant Melanoma (Cohorts 6a-c): Cohort Closed to Enrollment • Histologically or cytologically confirmed diagnosis of resectable cutaneous melanoma belonging to one of the following American Joint Committee on Cancer (AJCC) version 8 Tumor Node Metastasis (TNM) stages: Tx or T1-4 and N1b, or N1c, or N2b, or N2c, or N3b, or N3c and M0 • No prior radiotherapy or systemic anticancer therapy for melanoma • For Cohort 6c, participants must have at least one safely accessible lesion for IT injection of TransCon TLR7/8 Agonist that is ≥15 mm in the longest diameter
3. Neoadjuvant NSCLC (Cohort 7): • Histologically or cytologically confirmed NSCLC and must be ineligible for known actionable and available targeted therapy (e.g., epidermal growth factor receptor [EGFR]- mutations, anaplastic lymphoma kinase [ALK] rearrangement, or ROS1 rearrangements, or BRAF V600E mutation) and with completely resectable disease (tumors ≥4 cm or node positive) • No prior radiotherapy or systemic anticancer therapy for NSCLC • Evaluable disease with at least 1 measurable target lesion per RECIST 1.1 criteria
4. Post anti-PD-(L)1 NSCLC (Cohort 8): • Histologically or cytologically confirmed diagnosis of metastatic (stage IV) squamous or nonsquamous NSCLC • Must have progression of disease following treatment with platinum-based chemotherapy in addition to anti-PD(L)-1. • Must have received or be ineligible for known actionable and available targeted therapy (e.g., EGFR mutations, ALK rearrangement, ROS rearrangement, or BRAF V600E mutation). • Progression must be determined according to RECIST 1.1 while on anti-PD-(L)1 therapy or within 3 months of the last dose of anti-PD-(L)1 therapy • At least 1 target lesion of measurable disease per RECIST 1.1
5. Post anti-PD-(L)1 SCLC (Cohort 9): • Histologically or cytologically confirmed diagnosis of extensive stage SCLC. • Must have progression of disease following treatment with platinum-based chemotherapy in addition to anti-PD-(L)1. • Progression must be determined according to RECIST 1.1 while on anti-PD-(L)1 therapy or within 3 months of the last dose of anti-PD-(L)1 therapy. • At least 1 target lesion of measurable disease per RECIST 1.1.
6. 3L+ PROC (Cohort 14): TransCon IL-2 β/γ plus SOC Paclitaxel, Step-up RP2D Dosing: • Female participants with histologic or cytologic documentation of epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. • Must have PROC, defined as cancer progression within 6 months after completion of prior platinum-based therapy (at least 3 cycles). • Have received at least 2 lines of systemic therapy for ovarian cancer, including at least one platinum-based therapy. • At least 1 measurable target lesion as per RECIST 1.1.
7. 3L+ PROC (Cohort 15): TransCon IL-2 β/γ Monotherapy, Step-up RP2D Dosing • Female participants with histologic or cytologic documentation of epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. Carcinosarcoma, sarcoma, mucinous ovarian cancer, or low grade serous histologies are excluded. • Must have PROC, defined as cancer progression within 6 months after completion of prior platinum-based therapy (at least 3 cycles). Progression is defined by RECIST 1.1 criteria in association with symptoms necessitating treatment. • Have received at least 2 lines of systemic therapy for ovarian cancer, including at least one platinum-based therapy. • At least 1 measurable target lesion as per RECIST 1.1.
8. Post Anti-PD-1 Melanoma (Cohort 10): Cohort Closed to Enrollment • Must have unresectable (stage III) or metastatic (stage IV) melanoma who have progressed on anti-PD-1 therapy or had recurrence <6 months after adjuvant anti-PD-1 therapy • Progression must be determined according to RECIST 1.1 while on anti-PD-1 therapy or within 3 months of the last dose of anti-PD-1 therapy • At least 1 target lesion of measurable disease per RECIST 1.1
9. Metastatic Breast Cancer (Cohort 11) • Must have HER2+ metastatic breast cancer as defined by current American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) or local guidelines. • Have received at least 2 lines of anti-HER2 targeted therapies for metastatic disease setting • At least 1 target lesion of measurable disease per RECIST 1.1
10. Metastatic Breast Cancer (Cohort 12) • Must have HER2+ metastatic breast cancer as defined by current ASCO/CAP or local guidelines • Have received at least 2 lines of anti-HER2 targeted therapies for metastatic disease setting • At least 1 target lesion of measurable disease per RECIST 1.1
11. Metastatic Cervical Cancer (Cohort 13) • Must have extra-pelvic metastatic or recurrent cervical cancer with squamous cell, adenocarcinoma or adenosquamous histology, who are not candidates for curative therapy • Have received at least 1, but no more than 2 prior systemic treatment regimens for recurrent or metastatic cervical cancer. Chemotherapy administered in the adjuvant or neoadjuvant setting, or in combination with radiation therapy should not be counted as a prior systemic treatment regimen for recurrent or metastatic disease • At least 1 target lesion of measurable disease per RECIST 1.1
12. Part 2 and Part 4: • Tumor types where there is expected clinical activity of pembrolizumab in the advanced treatment setting and where participation in this clinical study is deemed by the investigator to be in the best interest of the participant compared to any other available therapies • No more than 2 lines of therapy or treatment regimens for locally advanced, unresectable, recurrent or metastatic disease
13. PROC (Cohort 3): Cohort Closed to Enrollment • Female participants with histologic or cytologic documentation of epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer • Must have PROC platinum-resistant ovarian cancer , defined as cancer progression within 6 months after completion of prior platinum-based therapy (at least 3 cycles) • At least 1 target lesion of measurable disease per RECIST 1.1
14. Post-PD-1 Melanoma (Cohort 4): Cohort Closed to Enrollment • Must have unresectable (stage III) or metastatic (stage IV) melanoma who have progressed on anti-PD-1 therapy or had recurrence <6 months after adjuvant anti-PD-1 therapy • Progression must be determined according to RECIST 1.1 while on anti-PD-1 therapy or within 3 months of the last dose of anti-PD-1 therapy • At least 1 target lesion of measurable disease per RECIST 1.1 and at least one safely accessible lesion for IT injection of TransCon TLR7/8 Agonist that is ≥15 mm in the longest diameter
15. Metastatic Cervical Cancer (Cohort 5): Cohort Closed to Enrollment • Must have extra-pelvic metastatic or recurrent cervical cancer with squamous cell, adenocarcinoma or adenosquamous histology, who are not candidates for curative therapy • Have received at least 1, but no more than 2 prior systemic treatment regimens for recurrent or metastatic cervical cancer. Chemotherapy administered in the adjuvant or neoadjuvant setting, or in combination with radiation therapy should not be counted as a prior systemic treatment regimen for recurrent or metastatic disease • At least 1 target lesion of measurable disease per RECIST 1.1
16. Post Anti-PD-1 Melanoma (Cohort 16): TransCon IL-2 β/γ Monotherapy, Step-up RP2D Dosing) • Histologically or cytologically confirmed diagnosis of unresectable (stage III) or metastatic (stage IV) melanoma who have progressed on anti-PD-1 therapy or had recurrence ≤12 weeks after adjuvant anti-PD-1 therapy. Acral/lentiginous and uveal melanoma are excluded. • Progression is defined as follows: 1. Required to have disease that has progressed on anti-PD-1, anti-lymphocyte activation gene 3 (LAG3), and anti-CTLA-4, either in combination(s) or sequentially (unless clinically contraindicated as deemed by the treating clinician or if not available locally). .2. Progression must be determined according to RECIST 1.1 while on anti PD 1 therapy or within 3 months of the last dose of anti-PD-1 therapy. • If participant is known to have BRAF-mutated disease, participant must have progressed on prior BRAF/MEK-directed therapy unless deemed clinically contraindicated by the treating clinician. • Have Stage III unresectable, M1a, or M1b disease per AJCC v8 (participants with M1c or M1d disease are not eligible). 1. M1a: distant metastasis to skin, soft tissue including muscles, and/or nonregional lymph nodes. 2. M1b: distant metastasis to lung with or without M1a sites of disease • Have had no more than 3 prior lines of therapy in the locally advanced unresectable or metastatic setting.

Exclusion criteria 1

1. • Prior treatment with IL-2 and variants (all participants) or TLR agonist (Part 3, Cohorts 4, 5, and 6c only) • Active autoimmune conditions • Significant cardiac disease • Symptomatic central nervous system metastases

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. "Incidence and severity of serious adverse events and adverse events (all Parts)"

Secondary endpoints 5

1. Parts 1 and 2; Part 3, Cohorts 3, 4, 5, 8, 9, 10, 11, 12, 13; and Part 4: • Objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST 1.1), duration of response (DoR), and time to response (TTR) per independent central review (ICR) • ORR by RECIST 1.1, DoR, and TTR per investigator assessment
2. Parts 1 and 2; Part 3, Cohorts 3, 4, 5, 8, 9, 10, 11, 12, 13; and Part 4: • Progression-free survival (PFS) by RECIST 1.1 per ICR • PFS by RECIST 1.1 per investigator assessment • Overall Survival (OS)
3. Part 3 Neoadjuvant Cohorts (melanoma in Cohorts 6a-c, and non-small cell lung cancer in Cohort 7) • ORR prior to surgery by RECIST 1.1 per ICR • ORR prior to surgery by RECIST 1.1 per investigator assessment • Pathologic complete response (pCR) per central assessment for pathology review
4. Part 3 Neoadjuvant Cohorts (melanoma in Cohorts 6a-c, and non-small cell lung cancer in Cohort 7): • Major pathologic response (MPR) per central assessment for pathology review • pCR per local assessment for pathology review • MPR per local assessment for pathology review • Event-free survival (EFS) by RECIST 1.1 per ICR • EFS by RECIST 1.1 per investigator assessment • OS
5. TransCon IL-2 β/γ and Free IL-2 β/γ PK parameters, alone or in combination with pembrolizumab, or SOC chemotherapy, or TransCon TLR7/8 Agonist, or in combination with pembrolizumab and SOC chemotherapy, or in combination with SOC trastuzumab or SOC trastuzumab emtansine (T-DM1)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Ascendis Pharma Oncology Division A/S

Sponsor organisation

Ascendis Pharma Oncology Division A/S

Address

Tuborg Boulevard 12

City

Hellerup

Postcode

2900

Country

Denmark

Scientific contact point

Organisation

Ascendis Pharma Oncology Division A/S

Contact name

Davis Torrejon-Castro

Public contact point

Organisation

Ascendis Pharma Oncology Division A/S

Contact name

Davis Torrejon-Castro

Third parties 14

Locations

4 EU/EEA countries · 35 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 94 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

9 submissions — initial application plus substantial / non-substantial modifications