FDA Issues New Guidance On Dose Optimization For Oncology Therapies

By Marjorie Zettler, Ph.D., MPH, senior director, clinical science, Accutar Biotech

Yet the approach to dose-finding for oncology drugs has changed little over the decades since cytotoxic chemotherapy drugs were first developed.³ The traditional paradigm for oncology drug dose selection centers on finding the maximum tolerated dose (MTD), the dose above which treatment-related toxicities occur that are so severe they preclude continued dose escalation. Phase 1 studies to identify the MTD usually enroll small numbers of patients, most commonly in a 3+3 design, with a new cohort escalating to a higher dose after a short interval to evaluate the occurrence of dose-limiting toxicities. This methodology made sense for cytotoxic chemotherapy drugs, which have steep dose-response curves, offer limited specificity, and are administered for relatively short durations, but the appropriateness of this strategy for newer oncology drugs is questionable. Most cancer therapies approved in recent years and currently in development are targeted therapies,⁴ which have different characteristics compared to cytotoxic chemotherapy drugs. Notably, targeted therapies may achieve target inhibition and produce an efficacious response at a dose much lower than the MTD, and because they tend to be administered for longer periods of time, the better tolerability of a dose lower than the MTD is desirable.

When oncology therapies are insufficiently characterized in advance of pivotal trials to support registration, the approved dose and schedule may be suboptimal. In this scenario, the FDA may issue post-marketing requirements (PMRs) for clinical trials evaluating additional dosages. Two recent examples are outlined below:

• Selinexor, in combination with dexamethasone, received accelerated approval in 2019 for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody.⁵ The recommended starting dosage was 80 mg taken on days 1 and 3 each week. At an Oncologic Drugs Advisory Committee meeting⁶ held prior to the approval, the FDA observed that there was “limited dose finding in KCP-330-001” [the Phase 1 dose escalation study⁷], and that in Part 2 of the Phase 2 KCP-330-012 (STORM) study,⁸ the “high rate of dose modifications and discontinuations suggests the optimal dose has not been identified.” The FDA issued the following PMR under the Food and Drug Administration Amendments Act (FDAAA) section 505(o)(3): “Conduct a randomized, Phase 2 clinical trial evaluating at least two lower doses or alternative dosage regimens of selinexor in combination with dexamethasone in patients with multiple myeloma to characterize and determine the rate of serious adverse reactions including myelosuppression, gastrointestinal toxicity, infection, hyponatremia, and neurological toxicity in all treatment arms…”⁹
• Sotorasib received accelerated approval in 2021 for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer who have received at least one prior systemic therapy, at a recommended dosage of 960 mg orally once daily.¹⁰ The approval relied on data from CodeBreaK 100, a first-in-human, single-arm, open-label Phase 1/2 trial with an expansion cohort design.¹¹ In the approval package, FDA reviewers noted that “considering the mechanism of action of the targeted therapy, the observed PK [pharmacokinetic] characteristics, the lack of clinical dose-response relationship for ORR [objective response rate], the potential GI [gastrointestinal] toxicity associated with the high oral dose, and the high daily pill burden for patients, further dose optimization to investigate a lower dosage that may provide comparable efficacy with improved safety as compared to 960 mg dose is warranted.”¹² The FDA issued the following PMR under FDAAA section 505(o)(3): “Conduct a multicenter, randomized clinical trial to further characterize serious adverse events, including gastro-intestinal toxicity and compare the safety and efficacy of sotorasib 960 mg daily versus a lower daily dose in patients with locally advanced or metastatic, KRAS G12C mutated, non-small cell lung cancer who have received at least one prior systemic therapy.”¹³

While PMRs for clinical studies of alternative dosages can be a fallback strategy for inadequately characterized therapies, ideally dose optimization would occur much earlier in development. To help facilitate this, the Project Optimus initiative was launched by the FDA’s Oncology Center of Excellence in 2019, aimed at modernizing dose finding and selection strategies in oncology drug development.¹⁴

Additionally, in January 2023, the FDA issued a new draft guidance document on optimizing the dosage of drugs and biological products for the treatment of oncologic diseases.¹⁵

Some key recommendations from the new draft guidance are summarized below:

• A PK sampling and analysis plan for the dose-finding trial should be prespecified and submitted to the FDA for review. The plan should be comprehensive enough to characterize the PK over multiple dosages, while also supporting population PK analyses, and dose- and exposure-response analyses for safety and efficacy. If appropriate for the indication and investigational product, a sampling and analysis plan for pharmacodynamic and pharmacogenomic data may be considered.
• The design and sample size of a trial to compare multiple dosages of the investigational product should permit assessment of safety, tolerability, and activity of each dosage. A randomized, parallel dose-response trial design is recommended, with an adaptive feature to allow for stopping enrollment in any arm where the dosage does not meet prespecified safety or efficacy standards during an interim analysis.
• Evaluation of safety and tolerability should include a comparison across dosages of dose interruptions, dose reductions, and drug discontinuations, in addition to serious adverse reactions. If safety monitoring indicates an emerging safety or tolerability issue, prespecified rules should delineate the actions that will be taken (e.g., pausing the trial, reducing the starting dose for subsequent patients, etc.). Lower-grade symptomatic treatment-related adverse events, such as diarrhea, that impact patients’ everyday lives and may prevent them from continuing therapy for extended periods of time, should be monitored and taken into account when determining the dosage for continued clinical development. If applicable, an alternate dosing strategy, such as titration to the intended therapeutic dose, may be considered to improve tolerability. Use of patient-reported outcome assessments during dose-finding studies also can provide an important perspective when deciding on dosages for further development.

In the race toward approval, particularly for therapies to treat rare cancers where there is significant unmet medical need and the new treatment is eligible for expedited programs such as breakthrough therapy or accelerated approval, the inclination may be to rush through the dose-finding process. However, a thoughtful approach and careful planning from the outset can prevent rework later. It also saves patients from unnecessary exposure to a dose that is poorly tolerated, adversely affects their quality of life, or hinders their ability to derive the full clinical benefit of the treatment.

References:

1. Patient-Centered Dosing Initiative. Accessed at: https://www.therightdose.org
2. Loeser AL, Peppercorn JM, Burkard ME, Kalinsky K, Rugo HS, Bardia A. Treatment-related side effects and views about dosage assessment to sustain quality of life: Results of an advocate-led survey of patients with metastatic breast cancer (MBC). J Clin Oncol. 2021; 39(15_suppl): 1005-1005. Accessed at: https://ascopubs.org/doi/abs/10.1200/JCO.2021.39.15_suppl.1005
3. Nie L, Rubin EH, Mehrotra N, Pinheiro J, Fernandes LL, Roy A, Bailey S, de Alwis DP. Rendering the 3 + 3 Design to Rest: More Efficient Approaches to Oncology Dose-Finding Trials in the Era of Targeted Therapy. Clin Cancer Res. 2016 Jun 1;22(11):2623-9. doi: 10.1158/1078-0432.CCR-15-2644.
4. Waarts MR, Stonestrom AJ, Park YC, Levine RL. Targeting mutations in cancer. J Clin Invest. 2022 Apr 15;132(8):e154943. doi: 10.1172/JCI154943.
5. XPOVIO prescribing information. Karyopharm Therapeutics, Inc. Newton, MA. July 2, 2019. Accessed at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212306s000lbl.pdf
6. Food and Drug Administration. Oncologic Drugs Advisory Committee meeting presentation materials. February 26, 2019. Accessed at: https://www.fda.gov/media/121670/download
7. ClinicalTrials.gov. Safety Study of the Selective Inhibitor of Nuclear Export (SINE) KPT-330 in Patients With Advanced Hematological Cancer. Accessed at: https://clinicaltrials.gov/ct2/show/NCT01607892
8. ClinicalTrials.gov. Selinexor Treatment of Refractory Myeloma (STORM). Accessed at: https://www.clinicaltrials.gov/ct2/show/results/NCT02336815
9. Food and Drug Administration. Selinexor ORIG-1 approval letter. July 2, 2019. Accessed at: https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2019/212306Orig1s000rplLTR.pdf
10. LUMAKRAS prescribing information. Amgen Inc., Thousand Oaks, CA. May 28, 2021. Accessed at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214665s000lbl.pdf
11. ClinicalTrials.gov. A Phase 1/2, Study Evaluating the Safety, Tolerability, PK, and Efficacy of Sotorasib (AMG 510) in Subjects With Solid Tumors With a Specific KRAS Mutation (CodeBreaK 100). Accessed at: https://clinicaltrials.gov/ct2/show/NCT03600883
12. Food and Drug Administration. Review package for sotorasib. May 28, 2021. Accessed at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/214665Orig1s000MultidisciplineR.pdf
13. Food and Drug Administration. Sotorasib ORIG-1 approval letter. May 28, 2021. Accessed at: https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2021/214665Orig1s000ltr.pdf
14. Food and Drug Administration. Project Optimus. Accessed at: https://www.fda.gov/about-fda/oncology-center-excellence/project-optimus
15. Food and Drug Administration. Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases. Guidance for Industry. January 2023. Accessed at: https://www.fda.gov/media/164555/download