Treatment of Solid Tumors Including Metastatic Breast Cancer

Citizen Petition Reconsider Issuance of RMAT Designation for Therapeutic Armed Activated T Lymphocytes Treatment of Solid Tumors including Metastatic Breast Cancer

The undersigned submits this petition under to request the Commissioner of Food and Drugs to reconsider issuing a Regenerative Medicine Advanced Therapy (RMAT) designation to autologous T-lymphocyte therapies for patients with malignant advanced stage solid tumors, specifically stage IV metastatic breast cancer, on the basis that it can meet an unmet medical need as substantiated by new clinical trial evidence resulting from trial involving OKT3 x Herceptin Armed Activated T Cells, Low Dose IL-2, and GM-CSF, as relevant to section 506(g) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), as added by section 3033 of the 21st Century Cures Act (Cures Act). A. Action Requested The Expedited Programs for Regenerative Medicine Therapies for Serious Conditions Draft Guidance for Industry states that in order for an investigational drug to receive a Regenerative Medicine Advanced Therapy (RMAT) designation it must fulfill the following criteria1:

• It meets the definition of regenerative medicine therapy (see section I of [draft guidance] document)
• It is intended to treat, modify, reverse or cure a serious condition; and
• Preliminary clinical evidence indicates that the regenerative medicine therapy has the potential to address unmet medical needs for such condition The Expedited Programs for Regenerative Medicine Therapies for Serious Conditions Draft Guidance for Industry states that the definition of regenerative medicine therapy is1: • Cell therapies, therapeutic tissue engineering products, human cell, and tissue products, and combination products using any such therapies or product And
• Gene therapies, including genetically modified cells, that lead to a durable modification of cells or tissues may meet the definition of a regenerative medicine therapy.

In said draft guidance, unmet medical need is defined as: • An unmet medical need is a condition whose treatment or diagnosis is not addressed adequately by available therapy. An unmet medical need includes an immediate need for a defined population (i.e., to treat a serious condition with no or limited treatment) or a longer-term need for society (e.g., to address the development of resistance to antibacterial drugs).

We, the undersigned, petition the Commissioner of Food and Drugs to reconsider issuing an RMAT designation to autologous T-Lymphocyte therapies for solid tumors, and we offer new clinical trial data from the trial named Treatment of Stage IV Breast Cancer With OKT3 x Herceptin Armed Activated T Cells, Low Dose IL-2, And GM-CSF (NCT00027807) as clinical evidence that indicates the potential to meet an unmet medical need thereby fulfilling the requirement “that the regenerative medicine therapy has the potential to address unmet medical needs for such condition” listed in The Expedited Programs for Regenerative Medicine Therapies for Serious Conditions Draft Guidance for Industry.1 B. Statement of Grounds Cancer is the second leading cause of death in the United States, with breast cancer following lung cancer as cancers with the highest mortality rates. While there have been a number of cancer therapies found to either treat or cure early-stage cancers, late-stage solid tumors tend to elude these therapies, and as a result, there are very few therapies that can attempt to treat them. Breast cancer is a disease that affects 1 out of 8 women, with 10% of all cases eventually metastasizing 5 years after the patient has received therapy for it.2,3 Many patients receive a form of therapy for breast cancer that may involve surgery with adjuvant chemotherapy, or even in the case of high-risk breast cancer high-dose chemotherapy with a stem cell transplant. Unfortunately, relapse rates after these therapies remain high, and often times the cancer has metastasized at that point. 55-87% of women who have primary breast cancer with 10 or more axillary lymph nodes relapse within 5 years of when they were diagnosed.

4 Stage IV metastatic breast cancer represents an unmet medical need, as it is not being met by current treatments or therapies. Additionally, there is research that indicates that combination therapies would work in a more effective manner against metastatic breast cancer than a single therapy.4 Some of the therapies that are currently being considered in clinical trials involve chimeric T cells, others are looking at armed activated T cells (aATC), and others are considering antibodies.3,4 The trial in question that we are using as the basis for our petition analyzes the combination immunotherapy consisting of HER2Bi armed activated T cell infusions, IL-2, and GM-CSF.3,4 The HER2Bi or BsAb consists of two monoclonal antibodies that were heteroconjugated and used to arm the T cells. These two monoclonal antibodies were Trastuzumab (Herceptin, Genentech) and an anti-CD3 (OKT3, Centocor, Ortho-Biotech) that were prepared under Current Good Manufacturing Practice (cGMP) regulations as enforced by the Food and Drugs Administration.5 Trastuzumab or the brand name Herceptin has been approved for use in the treatment of breast cancers that overexpress the HER2/neu receptor, which is a tyrosine kinase transmembrane epidermal growth factor receptor family member.3 The HER2/neu receptor is overexpressed in many breast, ovarian, gastric, lung, prostate and oral cancers. This overexpression of HER2/neu makes it an ideal therapeutic target.

3,4 Moreover, women with HER2- cancers have fewer therapeutic options, but the trial demonstrated a positive result in those patients as well, which further supports the claim that this therapy can fulfill an unmet need for a serious condition. The OKT3 or anti-CD3 antibody targets the CD3 T cell receptor. Together they form the HER2 Bispecific antibody (HER2Bi), which is engineered to direct cytotoxicity at tumor cells that overexpress the HER2/neu receptor. In this trial, they combined the HER2Bi with Interleukin-2 and the granulocyte macrophage colony-stimulating factor (GM-CSF). Interleukin-2 is a cytokine produced by leukocytes, which increases the growth and activity of other T lymphocytes and B-lymphocytes, as well as affecting the development of the immune system. GM-CSF is another cytokine that helps create additional white blood cells specifically granulocytes, macrophages, and cells that become platelets.3 The primary endpoints of the trial were to determine the safety and maximum tolerated dose. The highest dose that was administered consisted of 20 x 10^9 aATC, and the maximum tolerated dose level was not reached, nor were there any dose-limiting toxicities observed at this dosage level.

The secondary endpoints of the study were assessments of response rates: complete response (CR), stable disease (SD), partial response (PR), and no evidence of disease (NED), time to progression (TTP), and overall survival (OS). TTP and OS were measured from the date of enrollment in the trial.3 The study consisted of 23 women with stage IV metastatic breast cancer, of both HER2+ and HER2- patients, in a traditional 3+3 dose escalation design. One patient in the study died from digoxin toxicity related congestive heart failure, and the autopsy of the patient did not show any myocardial T cell infiltrates. The remaining 22 patients were evaluated at 14.5 weeks. Results showed 59.1% (13/22) of patients had SD or better (NED, PR, or SD) and 40.9% (9/22) of patients had PD. The overall survival rate of the 22 evaluable patients was 36.2 months. Within the overall survival rate, the breakdown was an overall survival rate of 57.4 months for HER2+ and 27.4 months for HER2-. The results of this study showed that there were no major negative side effects associated with this aATC therapy.

There were no cytokine storms, which has been a problematic side effect in past T-cell therapies, but there were however what the researchers designated cytokine flurries.3 And while a number of patients had to have their aATC washed to reduce side effects, not a single patient had to have their dose lowered. The main side effects observed were grade 3 chills and grade 3 headaches. The incidence of chills was 8.6%, 20.8%, and 43.1% at dose levels 1, 2, and 3, respectively. The incidence of headaches was 3.1%, 8.3%, and 19.6% at dose levels, 1, 2, and 3. Two patients were hospitalized to manage other side effects that included nausea, hypotension, vomiting, and dehydration, but after the successful resolution of these side effects they resumed the trial and continued to receive the infusions of the aATCs. In this trial, the innate cytotoxicity of T cells was redirected by the formation of the aATC (can be prepared with either CD4+ or CD8+,). Normal patients and cancer patients who received this combination therapy of aATC with HER2Bi combined with IL-2 and GM-CSF both exhibited specific cytotoxicity towards target cells, and the cytotoxicity increased as the dosage amount of the aATC increased.

4 The cytotoxicity persisted for more than 54 hours towards the target cells, and other cytokines including IFN-?, TNF- ?, and GM-CSF were induced when the tumor antigen was bound to the aATC.4 This capability of the aATC to induce IFN-? when it binds to a tumor antigen may be clinically beneficial, as other studies have already shown in preclinical and clinical studies that cytotoxic T cells produce IFN-? and that IFN-? is tumoricidal.6,7 Another advantage of this particular therapy is that it does not require large quantities of HER2Bi unlike other infusional therapies that do require large doses of bispecific antibodies. In fact, billions of armed activated T cells can be armed with just milligrams of the HER2Bi antibody. The aATCs proved to be cytotoxic even towards breast cancers that had a low expression level of HER2 receptors, such as the MCF-7 breast cancer cell line.

4 The SK-BR-3 cell line, which has higher levels of HER2 receptors, had even more susceptibility to cytotoxic effects from the aATC, causing greater amounts of tumor cells to be lysed.4 This indicates that even a small amount of the combination of the anti-CD3 and anti-HER2 antibodies that are used to arm activated T cells can mediate high levels of cytotoxicity that is directed at tumor cells. Even when the levels of the tumor antigen expression is low as in the case of the MCF-7 cell line, and are able to mediate cytotoxicity in vivo for many days after infusion of the aATCs.4 The fact that that the maximum tolerated dose was not reached, that there were no dose-limiting toxicities, nor was there any evidence of a life-threatening cytokine storm, and all other side effects were relatively mild and successfully resolved supports the idea that multiple infusions of aATC in combination with IL-2 and GM-CSF were both safe and technically feasible. The results of this study showed that combining antibody targeting and T cell-mediated killing could greatly augment cytotoxicity that can be directed towards cancer cells and provides a rationale to develop new nontoxic immunological approaches that can eradicate any residual tumor cells.

4 Ultimately the researchers have concluded that multiple intravenous infusions of the HER2Bi aATC are feasible, and most of them would go to the lungs and then migrate to, and settle, in the spleen, bone marrow, and liver. This is advantageous because many breast cancers metastasize to these locations, which would make the targeting of these metastases by the aATC easier. The authors of this study had intended on moving forward with a Phase II trial, and the results supported the rationale for moving forward. However, this trial ultimately did not move forward to a Phase II trial, but it did provide the rationale for further clinical trials on similar immunotherapies. A separate trial studied the HER2Bi armed activated T cells in HER2+ colorectal cancer, both in vitro and in vivo. The aATC exhibited increased cytotoxicity against HER2+ tumor cells, and showed significant suppression of colorectal carcinoma cells in comparison to unarmed ATC. Similar to the above-mentioned breast cancer trial, researchers were able to reach these results by using a very low dose of HER2Bi, which eliminated previously seen side effects of Herceptin which included cardiotoxicity that manifested as left ventricular dysfunction and heart failure in a different research project.

8 Much like the trial conducted on metastatic breast cancer, the data in this trial also showed that aATC induced IFN-? secretion levels that were higher than those induced by unarmed ATC, As such the researchers of this trial concluded that “HER2Bi?armed ATCs with anti?tumor effects may provide a promising immunotherapy for colorectal carcinoma for the future”.9 Another Phase I trial examined the HER2Bi aATC in metastatic castrate-resistant prostate cancer. They also found an increased level of IFN-? as well as no dose-limiting toxicities that were associated with this immunotherapy. 3 out of 7 patients in this trial showed a decrease in their prostate-specific antigen (PSA) and pain levels. The results of this trial provided strong rationale to continue onto a Phase II trial.10 Furthermore, there is another trial in progress that is also researching HER2Bi armed activated T cells combined with pembrolizumab, which blocks the PD-1 pathway, in patients with metastatic breast cancer. The trial (NCT03272334), sponsored by the University of Virginia is currently recruiting patients, but we look forward to seeing if it reaches its primary endpoints, which are evaluating the side effects and best dose for this treatment without reaching any dose-limiting toxicities.

11 While we need to keep a watchful eye on more severe side effects such as the possibility of life-threatening cytokine storms in future trials, the fact that the trial on metastatic breast cancer only had cytokine flurries is an encouraging sign. Novel immunotherapies including T-cell therapies are making headway as therapeutics for solid tumors and is a field that holds great promise because it can boost patients preexisting tumors responses, in a nontoxic manner, specifically in tumors that have no current successful therapy options.12 We would request that the Commissioner of Food and Drugs reconsider issuing an RMAT designation to autologous T-Lymphocyte therapies for solid tumors based on the preclinical trial data as covered above from the trial Treatment of Stage IV Breast Cancer With OKT3 x Herceptin Armed Activated T Cells, Low Dose IL-2, And GM-CSF (NCT00027807). We feel that this data, along with the fact that metastatic breast cancer is a serious condition that has very few therapies available to treat, and as such is an unmet medical need, fulfills all the requirements of an RMAT designation which are listed as:

• It meets the definition of regenerative medicine therapy (see section I of [draft guidance] document)
• It is intended to treat, modify, reverse or cure a serious condition; and
• Preliminary clinical evidence indicates that the regenerative medicine therapy has the potential to address unmet medical needs for such condition
• C. Environmental Impact The petitioner hereby states that the action requested in this petition will have no environmental impact and that, therefore, an environmental assessment is not required under 21 CFR 25.30.
• D. Economic Impact Not applicable; this section has not been requested by the Commissioner.
E. Certification The undersigned certifies, that, to the best knowledge and belief of the undersigned, this petition includes all information and views on which the petition relies, and that it includes representative data and information known to the petitioner which are unfavorable to the petition.

References

1. Food and Drug Administration. (2017, November). Expedited Programs for Regenerative Medicine Therapies for Serious Conditions Draft Guidance for Industry. Retrieved December 11, 2018, from https://www.fda.gov/downloads/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/guidances/cellularandgenetherapy/ucm585414.pdf 2. American Cancer Society. (n.d.). How Common Is Breast Cancer? Retrieved from https://www.cancer.org/cancer/breast-cancer/about/how-common-is-breast-cancer.html 3. Lum, L. G., Thakur, A., Al-Kadhimi, Z., Colvin, G. A., Cummings, F. J., Legare, R. D., . . . Rathore, R. (2015). Targeted T-cell Therapy in Stage IV Breast Cancer: A Phase I Clinical Trial. Clinical Cancer Research, 21(10), 2305-2314. doi:10.1158/1078-0432.ccr-14-2280 4. Sen, M., Wankowski, D. M., Garlie, N. K., Siebenlist, R. E., Epps, D. V., Lefever, A. V., & Lum, L. G. (2001). Use of Anti-CD3 × Anti-HER2/neu Bispecific Antibody for Redirecting Cytotoxicity of Activated T Cells Toward HER2/neu Tumors. Journal of Hematotherapy & Stem Cell Research, 10(2), 247-260. doi:10.1089/15258160151134944 5. Center for Drug Evaluation and Research. (n.d.). Manufacturing - Facts About the Current Good Manufacturing Practices (CGMPs). Retrieved from https://www.fda.gov/drugs/developmentapprovalprocess/manufacturing/ucm169105.htm 6. Ogawa M, W-G Yu, K Umehara, M Iwasaki, R Wijesuriya, T Tsujimura, T Kubo, H Fujiwara and T Hamaoka. (1998). Multiple roles of interferon-gamma in the mediation of interleukin 12-induced tumor regression. Cancer Res 58: 2426–2432. 7. Quian J-H, JA Titus, SM Andrew, D Mezzanzanica, MA Garrido, JR Wunderlich and DM Segal. (1991). Human peripheral blood lymphocytes targeted with bispecific anti- bodies release cytokines that are essential for inhibiting tumor growth. J Immunol 146:3250–3256. 8. Babar, T., Blomberg, C., Hoffner, E., & Yan, X. (2014). Anti-HER2 Cancer Therapy and Cardiotoxicity. Current Pharmaceutical Design,20(30), 4911-4919. doi:10.2174/1381612820666140604145037 9. Han, H., Ma, J., Zhang, K., Li, W., Liu, C., Zhang, Y., . . . Gao, B. (2014). Bispecific anti-CD3 x anti-HER2 antibody mediates T cell cytolytic activity to HER2-positive colorectal cancer in vitro and in vivo. International Journal of Oncology,45(6), 2446-2454. doi:10.3892/ijo.2014.2663 10. Vaishampayan, U., Thakur, A., Rathore, R., Kouttab, N., & Lum, L. G. (2015). Phase I Study of Anti-CD3 x Anti-Her2 Bispecific Antibody in Metastatic Castrate Resistant Prostate Cancer Patients. Prostate Cancer,2015, 1-10. doi:10.1155/2015/285193 11. ClinicalTrials.gov. National Library of Medicine (U.S.). (n.d.). Her2-BATS and Pembrolizumab in Metastatic Breast Cancer (Breast-47)r. Retrieved from https://clinicaltrials.gov/ct2/show/NCT03272334 12. Melton, C. (2018, November 28). Novel T-Cell Therapies Make Inroads Into Solid Tumors. Retrieved December 17, 2018, from https://www.onclive.com/publications/oncology-live/2018/vol-19-no-22/novel-tcell-therapies-make-inroads-into-solid-tumors?p=1

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