The dose escalation Phase 1 portion of the trial enrolled a total of 37 patients with cancers of different types. Nineteen patients were treated with one of four doses (25 mg, 50 mg, 75 mg or 100 mg once daily) of FLX475 monotherapy and 18 were treated with one of three doses (50 mg, 75 mg or 100 mg once daily) of FLX475 in combination with the standard dose of pembrolizumab. Disease control, defined as a best response of stable disease (SD), an unconfirmed or confirmed partial response (PR) or complete response (CR), was observed in 14 of the 17 evaluable monotherapy patients, including an unconfirmed partial response in a patient with relapsed metastatic cervical cancer. In the combination cohorts, disease control was observed in 13 of the 14 evaluable patients. This includes two confirmed partial responses: a patient with NSCLC who had progressed on prior checkpoint treatment (atezolizumab) and who remains on study after 18 months of treatment, and a patient with checkpoint inhibitor-naïve urothelial cancer who was on study for over nine months of treatment. In addition, preliminary data show an increase in the CD8 to Treg ratio after treatment, which is consistent with the hypothesis that a CCR4 antagonist can block the recruitment of tumor Treg, increase the CD8 to Treg ratio and potentially enhance antitumor immunity.
The Phase 1 results also show FLX475 had a favorable safety profile, with no maximum tolerated dose reached. Two dose-limiting toxicities (DLTs) of asymptomatic QTc prolongation were observed in the monotherapy cohorts, one in the 75 mg cohort and one in the 100 mg cohort. No DLTs were observed in the Phase 1 combination cohorts. Based on the Phase 1 data, 100 mg was selected as the recommended Phase 2 dose for both the monotherapy and combination therapy cohorts.
Phase 2 Data
The ongoing Phase 2 portion of the trial is enrolling a minimum of 80 patients with several types of charged tumors, 10 in each of eight cohorts, with four cohorts evaluating FLX475 as a monotherapy and four cohorts evaluating FLX475 in combination with pembrolizumab. The charged cancers include Epstein-Barr Virus (EBV)- or Human Papillomavirus (HPV)-associated cancers such as nasopharyngeal cancer, cervical cancer, and subsets of Hodgkin and non-Hodgkin lymphomas as well as head and neck cancer. Other charged tumor types include non-small cell lung cancer and triple-negative breast cancer. The protocol calls for expansion of cohorts to generate additional data based on promising clinical activity.
Based on the promising early results from the Phase 1/2 trial with FLX475 observed to date, RAPT has selected three cancer indications for expansion:
- EBV+ lymphoma – Early data from the first two patients with EBV+ lymphoma treated with FLX475 monotherapy show significant target tumor reduction, including one patient (1/2) who achieved a durable complete metabolic response and continues on study after more than nine months. RAPT plans to expand the EBV+ lymphoma monotherapy cohort and initiate a separate expansion cohort in EBV+ lymphoma in combination with pembrolizumab.
- Checkpoint inhibitor-naïve nasopharyngeal cancer (NPC) – Of the 10 evaluable patients with NPC treated with FLX475 monotherapy, seven of 10 (7/10) patients exhibited stable disease as best response. Seven of the 10 patients crossed over to combination therapy where significant clinical activity has been observed. Of the six evaluable patients who crossed over, five were checkpoint inhibitor naïve. All five (5/5) of the checkpoint inhibitor-naïve patients demonstrated significant tumor shrinkage, with three (3/5) of these patients showing a partial response (two confirmed and one unconfirmed). Based on these results, RAPT plans to open a combination cohort in checkpoint inhibitor-naïve NPC.
- Checkpoint inhibitor-naïve head and neck cancer – Of the 10 evaluable patients with head and neck cancers treated with FLX475 monotherapy, five of 10 (5/10) patients exhibited stable disease as best response. Six patients initially treated with monotherapy crossed over to combination therapy, with one achieving a partial response and a second patient with an unconfirmed partial response (2/6). Seventeen patients are enrolled in a separate combination treatment cohort, of which 10 are evaluable so far. Substantial tumor reduction has been observed in four of the 10 (4/10), including one confirmed complete response and three patients with greater than 20 percent tumor reduction. Based on these results, RAPT plans to expand the combination cohort in checkpoint inhibitor-naïve head and neck cancers.
