Tarlatamab + Radiation for Cancer

(RABBIT Trial)

Overseen By Rachel E Jarrett, MPH

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of Arizona

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: Interstitial lung disease, Pneumonitis, Autoimmune, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 2

Duration: Up to 24 months

30 Participants Needed

Trial Summary

What is the purpose of this trial?

Phase I study to examine safety of the addition of concurrent tarlatamab with standard palliative and consolidative RT regimens , with a main cohort of N=20-24 patients with extracranial anatomic radiation sites. I) After lead in of 10 patients demonstrating safety of treatment, allow for expansion to cranial sites of disease (N=6-10) with continued enrollment in main cohort II) If toxicity criteria is not met in concurrent RT tarlatamab cohort, we will continue with sequential RT, either A) delivered within 7 days prior to cycle 1 day 1, or B) delivered during cycle 1 -2 but with pre- and post-RT washout of 7 days with no drug during RT, to examine safety in a temporally spaced setting. III) If sequential tarlatamab and radiation is not deemed safe, we would allow for continued enrollment to assess efficacy of drug sans radiation treatment, enriching for tumors not of small cell lung cancer histology and allowing for patients without sites amenable to RT. A nested phase II study will attempt to assess for ORR and safety of study intervention amongst tumors not of small cell lung cancer histology.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, there is a 'washout period' (time without taking certain medications) of 7 days before and after radiation therapy during the first two cycles of treatment. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the treatment Tarlatamab + Radiation for Cancer?

Research suggests that combining radiation with immunotherapy, like Tarlatamab, can enhance the body's ability to fight cancer by boosting the immune system. Studies in other cancers, such as lung and melanoma, have shown that this combination can improve survival and reduce tumor recurrence. ^{1 2 3 4 5}

Is the combination of Tarlatamab and radiation therapy safe for humans?

The safety of combining immunotherapy and radiation therapy has been studied, but there are reports of serious side effects, including immune-related adverse events (irAEs) and treatment-related deaths. While these studies do not specifically mention Tarlatamab, they highlight potential risks when combining similar treatments. ^{6 7 8 9 10}

How is the treatment Tarlatamab + Radiation unique for cancer?

The combination of Tarlatamab, an immunotherapy drug, with radiation therapy is unique because it leverages the immune system to enhance the effects of radiation, potentially leading to better tumor control and the regression of distant metastases. This approach is novel as it combines the direct tumor-killing effects of radiation with the immune-boosting properties of Tarlatamab, aiming for a more comprehensive attack on cancer cells. ^{11 12 13 14 15}

Research Team

Charles Hsu, MD

Principal Investigator

University of Arizona

Ricklie Julian, MD

Principal Investigator

University of Arizona

Eligibility Criteria

This trial is for patients with various cancers, including lung, skin, and bladder cancer. Participants must have tumors expressing DLL3 and be suitable for radiation therapy. Specific eligibility criteria are not provided but typically include factors like age, health status, and prior treatments.

Inclusion Criteria

Subject has provided informed consent/assent prior to initiation of any study specific activities/procedures

I am 18 years old or older.

Minimum life expectancy of 12 weeks

Exclusion Criteria

I have not received any vaccines during the study period.

I don't have allergies to the study drugs and can attend all study visits.

I am not planning to conceive, and will follow the study's birth control requirements.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive tarlatamab with concurrent radiation therapy to extracranial sites, with dose escalation and monitoring for safety

Up to 24 months

Every 2 weeks (in-person)

Sequential Radiation Therapy

If concurrent therapy is not safe, participants receive sequential tarlatamab and radiation therapy with a 7-day washout period

Up to 24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Treatment Details

Interventions

• Concurrent Radiation Therapy
• Sequential Radiation therapy
• Tarlatamab

Trial Overview The study tests Tarlatamab combined with standard radiation therapy (RT), either given at the same time or sequentially. It starts with extracranial sites and may expand to cranial sites if safe. The goal is to assess safety first then efficacy, especially in non-small cell lung cancer types.

Participant Groups

Group I: Tarlatamab Monotherapy Cohort Experimental Treatment 1 Intervention

If the sequential safety endpoint is not met, then the study will proceed to another de-escalation phase, where 10 patients will receive tarlatamab alone.

Group II: Sequential radiation therapy cohort Experimental Treatment 2 Interventions

If the concurrent main cohort safety endpoint is not met, then the study will proceed to de-escalation, where 20 patients will be enrolled on the sequential radiation therapy cohort. In this cohort patients will receive sequential tarlatamab and RT to cranial and extracranial RT sites. Standard of care RT can occur prior to Cycle 1 Day 1(if radiation treatment is completed \<7 days prior to the start of tarlatamab) or be interdigitated with tarlatamab with a 7-day washout between RT and infusion, with RT to begin as early as Cycle 1 Day 22 and as late as cycle 2 Day 28, assuming no ongoing CRS/ICANS.

Group III: Concurrent Main Cohort Experimental Treatment 2 Interventions

Patients enrolled to this cohort will receive tarlatamab with concurrent radiation therapy (RT) to extracranial sites (n=20-24 extracranial RT with a minimum of 10 thoracic patients). Patients will receive tarlatamab at a step-up dose of 1 mg on Cycle 1 Day 1 and then 10 mg on cycle 1 Day 8 and Cycle 1 Day 15 and every 2 weeks thereafter (on days 1 and 15 of each cycle) until radiographic progression or disease progression or 24 months, whichever is earlier. Patients will receive concurrent RT to extracranial sites as per standard of care starting as early as Cycle 1 Day 16 and as late as Cycle 2 Day 28, assuming there is no ongoing cytokine release syndrome (CRS) or immune-effector cell-associated neurotoxicity Syndrome (ICANS).

Group IV: Concurrent Cranial Cohort Experimental Treatment 2 Interventions

If the safety endpoint in the Concurrent Main Cohort is met, enrollment will expand to the Concurrent Cranial Cohort. 6-10 patients will receive tarlatamab with concurrent radiation therapy to cranial sites as described in the Concurrent Main Cohort.

Who Is Running the Clinical Trial?

University of Arizona

Lead Sponsor

Trials

545

Recruited

161,000+

Amgen

Industry Sponsor

Trials

1,508

Recruited

1,433,000+

Founded

1980

Headquarters

Thousand Oaks, USA

Known For

Human Therapeutics

Top Products

Enbrel, Prolia, Neulasta, Otezla

Robert A. Bradway

Amgen

Chief Executive Officer since 2012

MBA from Harvard Business School

Paul Burton

Amgen

Chief Medical Officer since 2023

MD from University of London, PhD in Molecular and Cellular Biology from Imperial College London

Findings from Research

In a study of 44,498 patients with stage IV non-small-cell lung cancer (NSCLC), stereotactic radiotherapy (SRT) was associated with improved overall survival (OS), showing a hazard ratio of 0.78, indicating a significant benefit regardless of the type of systemic treatment used.

The combination of SRT and immunotherapy showed promising results, with patients receiving SRT having a median OS of 18.2 months compared to 14.3 months for those on chemotherapy, suggesting that SRT may enhance the effectiveness of immunotherapy and warrants further investigation in randomized trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overall survival according to immunotherapy and radiation treatment for metastatic non-small-cell lung cancer: a National Cancer Database analysis. Foster, CC., Sher, DJ., Rusthoven, CG., et al.[2020]

In a review of 16 melanoma patients treated with ipilimumab and cranial radiation, the combination was found to be well tolerated and associated with a median survival of 14 months, suggesting potential benefits for patients with brain metastases.

There was a notable trend indicating that administering ipilimumab within three months of radiation may enhance the likelihood of improved responses in extra-cranial lesions, warranting further investigation into the timing of these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilmumab and cranial radiation in metastatic melanoma patients: a case series and review. Schoenfeld, JD., Mahadevan, A., Floyd, SR., et al.[2022]

In a phase 2 trial involving 20 patients with metastatic melanoma, combining stereotactic body radiation therapy (SBRT) with nivolumab resulted in an overall response rate of 45%, indicating that this combination may enhance treatment efficacy.

The treatment was generally well tolerated, with most adverse events being mild (grade 1 to 2), and some patients showed delayed responses after SBRT, suggesting that this approach could benefit those who initially do not respond to nivolumab alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 Trial of Nivolumab Combined With Stereotactic Body Radiation Therapy in Patients With Metastatic or Locally Advanced Inoperable Melanoma. Sundahl, N., Seremet, T., Van Dorpe, J., et al.[2019]

A 74-year-old woman with lung adenocarcinoma developed fatal immune thrombocytopenia after receiving pembrolizumab following radiotherapy, highlighting a potential risk of severe immune-related adverse events (irAEs) when combining these treatments.

Flow cytometry analysis showed increased PD-1 and Ki-67 expression in T cells post-radiotherapy, suggesting that radiotherapy may enhance immune activation and contribute to the development of irAEs in patients undergoing anti-PD-1 therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab-related Immune Thrombocytopenia in a Patient with Lung Adenocarcinoma Treated by Radiotherapy: Potential Immune-related Adverse Event Elicited by Radiation Therapy. Tamanoi, D., Saruwatari, K., Imamura, K., et al.[2022]

In a study of 133 patients with metastatic cancers receiving immune checkpoint inhibitors and radiation, 34.6% experienced immune-related adverse events (ir-AEs), with higher rates observed in those receiving both CTLA-4 and PD-1 inhibitors (71% vs 29%).

The combination of palliative radiation and immune checkpoint inhibitors was generally well tolerated, with most ir-AEs being mild, suggesting that this treatment approach can be safely integrated in clinical practice for patients needing both therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter Evaluation of the Tolerability of Combined Treatment With PD-1 and CTLA-4 Immune Checkpoint Inhibitors and Palliative Radiation Therapy. Bang, A., Wilhite, TJ., Pike, LRG., et al.[2022]

In a study of 60 patients receiving combined immunotherapy and thoracic radiation therapy (iRT), no patients experienced severe grade ≥4 toxicities, indicating a favorable safety profile for this treatment approach.

While some patients did experience grade 3 toxicities, particularly pulmonary and hematologic issues, the overall short-term safety of iRT suggests it can be administered without significant risk of severe adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of Combined Immunotherapy and Thoracic Radiation Therapy: Analysis of 3 Single-Institutional Phase I/II Trials. Verma, V., Cushman, TR., Selek, U., et al.[2022]

Combining radiotherapy with immune treatment shows strong potential for enhancing the immune response against cancer, as radiation can increase the expression of key molecules that help the immune system recognize and attack tumors.

Preliminary clinical studies suggest that this combination therapy can effectively control local tumors and even lead to regression of distant metastases without significantly increasing side effects compared to using each treatment alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of radiotherapy and immune treatment: First clinical data. De Ruysscher, D.[2018]

Combining radiation therapy with immunotherapy shows great potential for enhancing cancer treatment, as preclinical studies suggest that radiation can make tumor cells more vulnerable to immune attacks.

Clinical trials have begun to support the idea that this combination can effectively boost antitumor immune responses, with ongoing studies exploring various therapeutic vaccines alongside radiation therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combining radiation and immunotherapy for synergistic antitumor therapy. Ferrara, TA., Hodge, JW., Gulley, JL.[2021]

Stereotactic ablative body radiotherapy (SABR) not only delivers high doses of radiation to tumors but also has significant immunomodulatory effects that can enhance the body's anti-tumor immune response.

Combining SABR with immune checkpoint inhibitors can improve treatment outcomes by overcoming tumor-induced immunosuppression and preparing tumors for a stronger adaptive immune response, as shown in early phase clinical studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The optimism surrounding stereotactic body radiation therapy and immunomodulation. Tharmalingam, H., Hoskin, PJ.[2018]

References

1. England pubmed.ncbi.nlm.nih.gov

Radiotherapy and immune checkpoint blockade: potential interactions and future directions. [2020]

2. England pubmed.ncbi.nlm.nih.gov

Overall survival according to immunotherapy and radiation treatment for metastatic non-small-cell lung cancer: a National Cancer Database analysis. [2020]

3. England pubmed.ncbi.nlm.nih.gov

Radiation therapy and immunotherapy: what is the optimal timing or sequencing? [2019]

4. England pubmed.ncbi.nlm.nih.gov

Ipilmumab and cranial radiation in metastatic melanoma patients: a case series and review. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Phase 2 Trial of Nivolumab Combined With Stereotactic Body Radiation Therapy in Patients With Metastatic or Locally Advanced Inoperable Melanoma. [2019]

6. Japan pubmed.ncbi.nlm.nih.gov

Pembrolizumab-related Immune Thrombocytopenia in a Patient with Lung Adenocarcinoma Treated by Radiotherapy: Potential Immune-related Adverse Event Elicited by Radiation Therapy. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Multicenter Evaluation of the Tolerability of Combined Treatment With PD-1 and CTLA-4 Immune Checkpoint Inhibitors and Palliative Radiation Therapy. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Safety of Combined Immunotherapy and Thoracic Radiation Therapy: Analysis of 3 Single-Institutional Phase I/II Trials. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Toxicity of radiation and immunotherapy combinations. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Prospective evaluation of the prognostic value of immune-related adverse events in patients with non-melanoma solid tumour treated with PD-1/PD-L1 inhibitors alone and in combination with radiotherapy. [2021]

11. France pubmed.ncbi.nlm.nih.gov

Combination of radiotherapy and immune treatment: First clinical data. [2018]

12. China pubmed.ncbi.nlm.nih.gov

Immunotherapy and radiotherapy for metastatic cancers. [2020]

13. England pubmed.ncbi.nlm.nih.gov

Combining radiation and immunotherapy for synergistic antitumor therapy. [2021]

14. England pubmed.ncbi.nlm.nih.gov

The Current and Future Role of Radiation Therapy in the Era of CAR T-cell Salvage. [2022]

15. China pubmed.ncbi.nlm.nih.gov

The optimism surrounding stereotactic body radiation therapy and immunomodulation. [2018]