A phase 2 study of GI-6207 in patients with recurrent medullary thyroid cancer

Abstract

Background

Medullary thyroid cancer (MTC) accounts for approximately 4% of thyroid carcinomas. Patients with unresectable, metastatic disease are candidates for approved agent-targeted therapies such as vandetanib, cabozantinib, or selpercatinib, but toxicity is often an issue. Preclinical data supported the potential use of immunotherapy targeting carcinoembryonic antigen (CEA) in this indolent disease.

Methods

Patients with advanced/recurrent MTC were randomly assigned in a 1:1 ratio to receive a Saccharomyces cerevisiae (yeast)-based immunotherapy (GI-6207) targeting CEA starting at the time of enrollment or 6 months after surveillance. The primary endpoint was to compare the calcitonin growth rate in the GI-6207 arm at 6 months with patients in the surveillance arm at 6 months.

Results

Between March 2013 and May 2018, 34 patients were randomly assigned to receive the yeast-CEA vaccine (GI-6207) starting at the time of enrollment or 6 months after surveillance. The mean age was 51 years, and 82% of patients were diagnosed with sporadic MTC. There was no significant change in the calcitonin growth rates at 6 months when the immunotherapy group was compared with the surveillance group (−2.490042 vs −2.526385; P = .3760). Treatment with GI-6207 was associated with increased peripheral CEA-specific CD4 and/or CD8 T cells, with 15/26 (58%) patients displaying increases after 3 months of treatment. One patient had a significant inflammatory event 17 months after the last vaccine at a known lymph node, perhaps related to a delayed immune response. There were no grade 3 or 4 adverse events. Grade 1 injection site reactions were most common.

Conclusion

The immunotherapy was well tolerated but did not have an impact on tumor growth rate at 6 months as measured by calcitonin kinetics.

Clinical Trial Identification

NCT01856920

Lessons Learned.

• GI-6207 is well tolerated.

• There was no short-term impact on tumor growth rates as measured by serum calcitonin.

• Activation of peripheral CEA-specific T-cells was seen in 58% of patients 3 months after receiving GI-6207.

• Similar to the phase 1 trial, there was an inflammatory event at the site of the tumor, perhaps signifying an immune response.

Trial information

Trial information
Disease	Relapsed medullary thyroid cancer after resection
Stage of disease/treatment	IV
Prior therapy	Prior surgery
Type of study	Phase II
Primary endpoints	Change in tumor growth rate
Secondary endpoints	Immune responses, progression free survival
Study design:  Patients were randomized 1:1 to either immediate GI-6207 or surveillance for 6 months followed by treatment with GI-6207. Patients were re-staged every 3 months while on treatment. For patients on the surveillance arm, they were re-staged prior to initiating treatment after completing surveillance. Additional details for primary end point:  The primary endpoint was the change from baseline to 6 months of the tumor growth rate parameter measured by serum calcitonin as previously described.1 At baseline and at 6 months after randomization, there was 80% power to detect a difference between the two groups with respect to a change from baseline to 6 months equal to 1.0 standard deviations of the change (1.0 effect size) using a two-tailed 0.05 level two-sample t-test.

Drug information

Drug information
Generic/working name	GI-6207
Drug class	Immunotherapy
Dose	40 yeast units divided into 4 injections (10 yeast units per injection)
Route	Subcutaneously
Schedule of administration	Treatment was biweekly for 7 visits (day 1, 15, 29, 43, 57, 71, 85), then monthly for up to 1 year of treatment. An amendment to the study later added boosters every 3 months for a year (4 doses) after patients completed 1 year of treatment.

Baseline Demographics and Patient Characteristics
Characteristics	Surveillance arm		Vaccine arm
	No	%	No	%
Sex
Male	9	50	6	38
Female	9	50	10	62
ECOG
0	13	72	11	69
1	5	28	5	31
Disease type
Locally advanced	2	11	5	31
Metastatic	16	89	11	69
RET mutation
Positive	4	22	3	19
Negative	8	45	5	31
Unknown	6	33	8	50

Outcomes

With regard to the primary endpoint, there was no significant change in the calcitonin growth rate kinetics at 6 months when the immunotherapy group was compared with the surveillance group (−2.490042 vs −2.526385; P = .3760) per the protocol-defined methodology that has been previously described. The proportion of patients free of progression at 2 years was similar in the two groups of initial vs deferred immunotherapy. For the initial treatment arm it was 73.3% (11 of 15 evaluable patients) vs 70% (7 of 10 evaluable patients) in the deferred treatment arm. Among all patients treated with GI-6207, 15 of 26 patients (58%) had an increase in CEA-specific CD4 and/or CD8 T-cells 3 months after receiving GI-6207. Of note, among 9 patients with disease progression on-study, 7 were evaluable for CEA-specific immune responses, and 5 of them had no CEA-specific immune responses, while 2 had minimal responses to only one parameter (Figure 1).

Figure 1.

Peripheral CEA-specific T cells developed after 3 months of GI-6207 therapy. Immune responses reported in this table are calculated by comparing the absolute number of CD4+ or CD8+ T cells producing cytokine (IFNg, IL-2, TNFa) or positive for CD107a after in vitro stimulation with overlapping 15-mer CEA peptides per 1 × 106 PBMCs plated at the start of in vitro stimulation. Any background signal (obtained with a negative control peptide pool, human leukocyte antigen [HLA]) and any response prior to treatment with GI-6207 are subtracted: [CEA response post GI-6207—HLA response post GI-6207]—[CEA response pre GI-6207–HLA response pre GI-6207]. Positive immune responses are defined as >250 cells (+). Abbreviations: IFNg, interferon gamma; IL-2, interleukin-2; TNFa, tumor necrosis factor alpha.

Treatment related adverse events
	Grade 1	Grade 2	Grade 3	Grade 4/5
Injection site reaction	19	7	0	0
Fatigue	9	2	0	0
Flu like symptoms	8	0	0	0
Diarrhea	7	2	0	0
Nausea	6	1	0
Myalgia	6	0	0	0
Fever	3	0	0	0
Pruritus	3	1	0	0
Hyponatremia	2	0	0	0
Nasal congestion	2	0	0	0
Anemia	2	0	0	0
Postnasal drip	1	0	0	0
Allergic rhinitis	1	0	0	0
Elevated aspartate aminotransferase	1	0	0	0
Neck edema	0	0	1	0
Neck pain	0	1	0	0
Thrombocytopenia	1	0	0	0
Lymphopenia	1	0	0	0
Headache	1	0	0	0
Abdominal pain	0	1	0	0
Arthralgia	1	0	0	0
Facial muscle weakness	1	0	0	0
Cardiac	1	0	0	0
Vascular	1	0	0	0

Discussion

Despite supporting preclinical data, this study of GI-6207, an antigen-directed immunotherapy against CEA, did not meet its primary endpoint of altering tumor growth rates within 6 months as measured by serum calcitonin.^2,3 The study’s primary hypothesis was that antigen-directed immunotherapies may have less impact on shrinking tumors, but may yield improved clinical outcomes by slowing down the growth of tumors based on immunologic response.⁴ The data from this fully enrolled study did not support that hypothesis, as the calcitonin growth rate was not significantly impacted at 6 months. The treatment was well tolerated with mostly injection site reactions and flu-like symptoms, consistent with the phase 1 experience with this immunotherapy.⁵

There were no overall responses for patients on imaging while on treatment, nor were there significant (greater than 50%) sustained declines in serum CEA or calcitonin levels. There was evidence of immunologic activity, with induction of peripheral CEA-specific CD4 and/or CD8 T cells in 15/26 (58%) patients evaluated. One patient did, however, have a significant inflammatory event at a known lymph node site of disease 17 months after therapy (Figure 1). This lymph node was biopsied and only revealed immune cells, but no tumor, signifying this was not disease progression (Figures 2 and 3). There were also no clinical symptoms consistent with an infection. This lymph node inflammation resolved spontaneously within a week. This is not a common occurrence in medullary thyroid cancer. A similar inflammatory response at the site of disease was seen in a patient in the phase 1 trial of GI-6207 and was thought to be related to a possible anti-tumor immune response.⁵ In addition, delayed responses have been noted in antigen-directed immunotherapy studies with prostate cancer as well.^6,7

Figure 2.

Transient inflammation 17 months after immunotherapy. (A) Arrow defines known site of disease on computed tomography (CT). (B) Arrow shows clinically evident inflammation of 17 months after the vaccine on a CT (the patient had no other therapies over the 17 months). (C) CT shows resolution of swelling within a week after inflammation in this patient who had no signs of infection and was not treated with anything for this inflammation.

Figure 3.

Biopsy of inflamed lymph node. Biopsy of the enlarging lymph node showing lymphoid tissue, hyperplastic with focal areas of necrosis. Tumor markers TTF-1 and calcitonin stains are negative. Robust expression of CD3 (A) and CD20 (B) by immunohistochemistry.

Future studies may be considered with GI-6207 to capitalize on its potential to induce antigen-specific T-cells and perhaps inflammatory immune responses at sites of disease. Further understanding of the inflammatory phenomenon could enhance the therapeutic efficacy of GI-6207, perhaps in combination with other agents.

Author contributions

Jaydira Del Rivero (Data curation, Formal analysis, Investigation, Writing—review & editing), Renee N. Donahue (Data curation, Formal analysis, Investigation, Methodology, Project administration, Validation, Writing—original draft, Writing—review & editing), Jennifer L. Marte (Data curation, Investigation, Writing—review & editing), Ann Gramza (Data curation, Formal analysis, Investigation, Writing—review & editing), Marijo Bilusic (Data curation, Investigation, Writing—review & editing), Lisa Cordes (Data curation, Investigation, Writing—review & editing), Fatima Karzai (Data curation, Investigation, Writing—review & editing), Jeffrey Schlom (Data curation, Funding acquisition, Investigation, Writing—review & editing), James L. Gulley (Data curation, Funding acquisition, Investigation, Writing—review & editing), and Ravi Madan (Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing—original draft, Writing—review & editing)

Funding

This research was supported [in part] by the Intramural Research Program of the National Institutes of Health (NIH). The contributions of the NIH author(s) were made as part of their official duties as NIH federal employees, are in compliance with agency policy requirements, and are considered Works of the United States Government. However, the findings and conclusions presented in this paper are those of the author(s) and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services. This study was funded by the NCI Intramural Program and a collaborative research and development agreement between the NCI and Globeimmune, Inc.

Conflict of interest

No authors have conflicts of interest.

Data Availability

Data supporting the results reported in this article, will be made available from the completed study within 6 months from initial request to researchers who provide a methodologically sound proposal. The data will be provided after its de-identification, in compliance with applicable privacy laws, data protection, and requirements for consent and anonymization.