STING Agonist and Personalized Ultra-fractionated Stereotactic Adaptive Radiotherapy in Combination With Checkpoint Inhibition for Patients With Metastatic Kidney Cancer (SPARK)

To evaluate progression of metastatic renal cell carcinoma from the initiation of PULSAR radiotherapy in combination with IMSA101 injectable onward.

More details:

The study expects to accrue the 20 patients over a 3-4 year period. Patients with oligoprogressive disease (1-3 lesions) after treatment with Anti-PD1 / Anti-CTLA-4 will continue Anti-PD1 (nivolumab). All patients will have a mandatory PD-L1 PET (Pre-treatment and Week 12). All patients will undergo baseline biopsy (just before the administration of IMSA101 of the same lesion to be injected). SAbR will be delivered in 3 fractions at 12 Gy every 4 weeks (PULSAR regimen) to all progressing lesions. One lesion will also receive 5 intratumoral injections of IMSA101 (C1D1, C1D8, C1D15, C2D1, C3D1) immediately after radiation either on the same day or within 72 hours after the PULSE. Selected Phase 2 dosing of IMSA101 (1200mcg) will be utilized. At disease progression, patients have the option to undergo additional imaging and tissue/blood collections.

Overview

IMSA101 (also known as GB492) is an intratumorally administered small‑molecule cyclic dinucleotide STING agonist being developed for solid tumors, including in combinations with immune checkpoint inhibitors and radiotherapy. A first‑in‑human phase 1 study in advanced solid tumors has been published (J Immunotherapy of Cancer, June 18, 2025). (pubmed.ncbi.nlm.nih.gov)

Mechanism of action

• Target: STING (TMEM173). IMSA101 is a cGAMP analog that activates the cGAS–STING pathway, inducing type I interferons and pro‑inflammatory cytokines to promote antigen presentation and T‑cell–mediated antitumor immunity. (pubmed.ncbi.nlm.nih.gov)
• Preclinical data: In murine models, intratumoral IMSA101 enhanced CAR‑T antitumor function, associated with induction of IL‑18. (pubmed.ncbi.nlm.nih.gov)

Clinical development

• Phase 1/1b/2a (NCT04020185): open‑label, intratumoral IMSA101 as monotherapy and in combination with a PD‑(L)1 inhibitor; 40 patients treated. Results published in 2025 (details below). (pubmed.ncbi.nlm.nih.gov)
• Randomized phase 2 trials combining PULSAR radiotherapy + PD‑1 inhibitor ± IMSA101 were initiated in 2023:
• Oligometastatic NSCLC/RCC (NCT05846646) and oligoprogressive solid tumors (NCT05846659); designs reported in an ASCO 2024 abstract. As of late 2024, registry listings indicate both studies reached primary completion; postings in some registries list the status as terminated, and no results are posted on ClinicalTrials.gov yet as of October 7, 2025. (ascopubs.org)

Efficacy (human data to date)

Phase 1 first‑in‑human, intratumoral IMSA101 (n=40; 22 monotherapy, 18 combination with PD‑(L)1 inhibitor):
- Monotherapy: no confirmed complete or partial responses; best response was stable disease in 1/22 (4.5%); 17/22 (77.3%) had progressive disease as best response. (pubmed.ncbi.nlm.nih.gov)
- Combination therapy: overall response rate 5.6% (1/18); remaining patients had progressive disease (55.6%) or stable disease (11.1%). Authors concluded antitumor activity signals were minimal in this heterogeneous, heavily pretreated population. (pubmed.ncbi.nlm.nih.gov)

No randomized efficacy data are available yet from the PULSAR‑ICI ± IMSA101 phase 2 studies; results have not been posted as of October 7, 2025. (fdaaa.trialstracker.net)

Safety

From the phase 1 study (intratumoral dosing up to 1,200 µg monotherapy and 2,400 µg with ICI):
- Most common treatment‑related adverse events: injection‑site pain and fatigue (monotherapy); chills, injection‑site pain, and fever (combination). A clear dose‑AE relationship was not observed. (pubmed.ncbi.nlm.nih.gov)
- Pharmacokinetics: short plasma half‑life (~1.5–2 hours) without accumulation. (pubmed.ncbi.nlm.nih.gov)

Notes and context

• Route and schedule used clinically: intratumoral injections weekly for the first 3 weeks, then every 2 weeks; recommended phase 2 doses selected were 1,200 µg (monotherapy) and 2,400 µg (with ICI). (pubmed.ncbi.nlm.nih.gov)
• Rationale for combinations: preclinical and translational data support pairing STING activation with checkpoint blockade and with radiation; randomized PULSAR‑ICI ± IMSA101 trials were designed to test this clinically. (ascopubs.org)

Further reading

• Phase 1, first‑in‑human results (J Immunotherapy of Cancer, 2025). (pubmed.ncbi.nlm.nih.gov)
• Nature Communications (2024): IMSA101 enhances CAR‑T function via IL‑18. (pubmed.ncbi.nlm.nih.gov)
• ASCO 2024 trials‑in‑progress abstract describing the two randomized phase 2 PULSAR‑ICI ± IMSA101 studies. (ascopubs.org)
• Trial registry snapshots for phase 2 studies (status/primary completion dates; results pending): NCT05846646, NCT05846659. (ichgcp.net)
• Background on the STING pathway in cancer immunity. (ncbi.nlm.nih.gov)

Last updated: Oct 2025

Inclusion Criteria:

* Patients must have metastatic ccRCC.

* Patients must have oligoprogression defined as progression in ≤3 lesions.

* All oligoprogression lesions must be suitable for radiation.

* Patients must have at least one site of disease that can be safely injected with IMSA101. Lung metastases are excluded.

* ECOG performance status 0-2.

* Age ≥ 18 years.

* Patients must have adequate organ and marrow function within 14 days prior to study entry.

* All IMDC risk categories are allowed.

Exclusion Criteria:

* Patients with progressive ultracentral/central chest lesions will be excluded