NCT06708455

Phase 2b of RAPA-201 Cell Therapy in Post-PD-(L)-1 Melanoma

Phase 2 Trial of Autologous Rapamycin-Resistant Th1/Tc1 (RAPA-201) Cell Therapy of PD-(L)1 Resistant Malignant Melanoma

• Status: Not Yet Recruiting
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 65 (estimated)
• Sponsor: Rapa Therapeutics LLC · Industry
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

The protocol is a Simon's 2-stage, non-randomized, open label, multi-site, phase 2 trial for patients with advanced metastatic, recurrent and unresectable malignant melanoma that has recurred or relapsed after prior anti-PD-(L)1 therapy.

Detailed description

The therapy of solid tumors, including melanoma, has been revolutionized by immune therapy, in particular, approaches that activate immune T cells in a polyclonal manner through blockade of checkpoint pathways such as the PD-1/PD-L1 pathway \[PD-(L)1\] by administration of monoclonal antibodies. In this study, we will evaluate the adoptive transfer of RAPA-201 cells, which are checkpoint-deficient polyclonal T cells that represent an analogous yet distinct immune therapy treatment platform for the therapy of malignant melanoma that is refractory to anti-PD-(L)1 therapy. RAPA-201 is a second-generation immunotherapy product consisting of epigenetically reprogrammed autologous CD4+ and CD8+ T cells of Th1/Tc1 cytokine phenotype. RAPA-201, which is safely administered exclusively in the outpatient setting, is currently being evaluated for the therapy of solid tumors that are refractory to anti-PD-(L)1 therapy (NCT05144698), with accrued patients having diagnoses of non-small cell lung cancer, small cell lung cancer, squamous cell head and neck and cancer, gastric cancer, esophageal cancer, and melanoma. Because RAPA-201 is a polyclonal T cell therapy that targets potential tumor antigens in vivo, RAPA-201 may also be applicable for the therapy of other immune sensitive tumors, including but not limited to lung cancer, bladder cancer, and renal cell carcinoma. Initial results on the first RAPA-201 clinical trial in solid tumors (NCT05144698) demonstrated that six out of 10 evaluable melanoma patients (60%) responded to RAPA-201 therapy, thus providing a rationale for this phase 2b clinical trial that will focus exclusively upon the treatment of PD-(L)1 refractory malignant melanoma. On the basis of these results, RAPA-201 therapy of treatment-refractory metastatic melanoma was granted the Regenerative Medicine Advanced Therapy (RMAT) designation by the US FDA. The novel RAPA-201 manufacturing platform, which incorporates both an inhibitor of the mechanistic target of rapamycin (mTOR; temsirolimus) and an anti-cancer Th1/Tc1 polarizing agent (IFN-alpha) generates polyclonal T cells with five key characteristics: 1. Th1/Tc1: polarization to anti-cancer Th1 and Tc1 subsets, with commensurate down-regulation of immune suppressive Th2 and regulatory T (TREG) subsets; 2. T Central Memory: expression of a T central memory (TCM) phenotype, which promotes T cell engraftment and persistence for prolonged anti-tumor effects; 3. Rapamycin-Resistance: which translates into a multi-faceted anti-apoptotic phenotype that improves T cell fitness in the stringent conditions of the tumor microenvironment; the resistant phenotype of RAPA-201 also permits concomitant therapy with cytotoxic chemotherapy, including the outpatient carboplatin plus paclitaxel regimen utilized on this protocol or planned combination therapy with tumor targeted antibody drug conjugates (ADCs); 4. T Cell Quiescence: reduced T cell activation, as evidence by reduced expression of the IL-2 receptor CD25, which reduces T cell-mediated cytokine toxicities such as cytokine-release syndrome (CRS) that limit other forms of T cell therapy; and 5. Reduced Checkpoints: multiple checkpoint inhibitory receptors are markedly reduced on RAPA-201 cells (including but not limited to PD-1, CTLA4, TIM-3, LAG3, and LAIR1), which increases T cell immunity in the checkpoint-replete, immune suppressive tumor microenvironment; RAPA-201 follows the normal rules of immunology, with eventual checkpoint expression after RAPA-201 maturation from a TCM phenotype towards a T effector memory phenotype; because of this biology, we envision that RAPA-201 will be favorably incorporated into anti-PD-(L)1 containing combination regimens.

Conditions

• Malignant Melanoma With Metastasis
• Malignant Melanoma
• Malignant Melanoma Stage IIIc
• Malignant Melanoma Stage IV

Interventions

Type	Name	Description
BIOLOGICAL	RAPA-201 Rapamycin Resistant T Cells	Autologous Rapamycin-Resistant Th1/Tc1 Cells
DRUG	Chemotherapy Prior to RAPA-201 Therapy	Carboplatin + Paclitaxel Regimen (CP Regimen)

Timeline

• Start date: 2027-03-01
• Primary completion: 2029-03-01
• Completion: 2029-09-30
• First posted: 2024-11-27
• Last updated: 2026-03-19

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study