Cabozantinib + 177Lu-PSMA-617 for Prostate Cancer

(CaboLu Trial)

Overseen By Susan Sharry

Age: 18+

Sex: Male

Trial Phase: Phase 1

Sponsor: University of Utah

Must be taking: Androgen-deprivation therapy

Must not be taking: Anticoagulants, Anticancer agents

Disqualifiers: Brain metastases, Uncontrolled hypertension, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

33 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effectiveness of combining two treatments, cabozantinib (a cancer medication) and 177Lu-PSMA-617, for advanced prostate cancer that has spread despite hormone therapy. Researchers aim to determine the safest and most effective dose of cabozantinib to use with 177Lu-PSMA-617. Men with advanced prostate cancer, who have already tried hormone therapy and whose cancer continues to progress, might be suitable for this study. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it mentions a washout period (time without taking certain medications) for prohibited medications before starting the treatment. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that cabozantinib, when combined with other treatments, has side effects that patients with advanced prostate cancer can generally handle. In these studies, patients managed the treatment well and showed significant improvement in their cancer. While the drug has some side effects, it is usually well-tolerated.

For 177Lu-PSMA-617, studies have found it can help patients with prostate cancer live longer. It is generally considered safe, though it may have side effects like any treatment. Most patients complete their treatment cycles, indicating that the drug is manageable for many.

Overall, these findings suggest that both cabozantinib and 177Lu-PSMA-617 are relatively safe for patients, with side effects that are usually manageable. Participants considering joining a trial with these treatments can feel somewhat reassured by their safety records in other studies. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Cabozantinib with 177Lu-PSMA-617 for prostate cancer because it offers a novel approach compared to standard treatments like hormone therapy and chemotherapy. Cabozantinib works by inhibiting specific proteins that help cancer cells grow and spread, while 177Lu-PSMA-617 is a radioligand therapy that targets and delivers radiation directly to prostate cancer cells. This dual action not only aims to shrink tumors but also limits damage to healthy tissue, potentially leading to better outcomes with fewer side effects. This innovative combination targets cancer more precisely, offering hope for more effective and safer treatment options.

What evidence suggests that cabozantinib + 177Lu-PSMA-617 might be an effective treatment for prostate cancer?

Research has shown that cabozantinib, one of the treatments studied in this trial, may help treat advanced prostate cancer. It has been linked to shrinking tumors and improving bone scans in patients with metastatic cancer. When combined with another treatment, cabozantinib lowered the risk of disease progression or death by 35%.

Regarding 177Lu-PSMA-617, another treatment under investigation in this trial, studies have found promising results in reducing pain and improving scan results. Patients treated with 177Lu-PSMA-617 demonstrated significant improvements, with some experiencing complete or partial recovery. These findings suggest that both cabozantinib and 177Lu-PSMA-617 could effectively treat prostate cancer that has spread and is resistant to standard hormone therapy. ^{1 4 6 7 8}

Who Is on the Research Team?

Umang Swami, MD

Principal Investigator

Huntsman Cancer Institute

Are You a Good Fit for This Trial?

Men over 18 with advanced prostate cancer that's resistant to hormone therapy and has spread. They must have had specific prior treatments, including hormone therapies and chemotherapy, show PSMA-positive lesions, be in good physical condition (ECOG ≤1), have proper organ function, and agree to use contraception. Excluded are those with certain severe illnesses or recent surgeries, uncontrolled hypertension, brain metastases not stable for 4 weeks, active infections like HIV or hepatitis B/C.

Inclusion Criteria

Able to provide informed consent and willing to sign an approved consent form

Sexually active fertile patients and their partners must agree to use medically accepted methods of contraception

Life expectancy >3 months

Exclusion Criteria

Receiving other investigational anti-cancer agents

Medical, psychiatric, cognitive, or other conditions that may compromise study participation

I have been treated with cabozantinib before.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Part 1 will assess the rate of dose-limiting toxicities (DLTs) during the DLT evaluation period and identify the MTD and/or recommended dose and schedule

4 weeks

Dose Expansion

Expansion Phase to assess identified MTD and schedule from Part 1

24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

38 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Cabozantinib

Trial Overview The study is testing different doses of Cabozantinib combined with a radioactive drug called Lutetium-177 PSMA-617 on men with metastatic castration-resistant prostate cancer (mCRPC). It aims to find the highest dose patients can take without serious side effects (MTD) before expanding the trial.

How Is the Trial Designed?

Group I: Dose Expansion Cohort (Part 2) Experimental Treatment 1 Intervention

Expansion Phase to assess identified MTD and schedule from Part 1.

Group II: Dose Escalation (Part 1) Experimental Treatment 1 Intervention

Part 1 will assess the rate of dose-limiting toxicities (DLTs) during the DLT evaluation period and identify the MTD and/or recommended dose and schedule

Cabozantinib is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Cabometyx for:

• Renal cell carcinoma
• Hepatocellular carcinoma

Approved in United States as Cabometyx for:

• Renal cell carcinoma
• Hepatocellular carcinoma

Approved in Canada as Cabometyx for:

• Renal cell carcinoma
• Hepatocellular carcinoma

Approved in Japan as Cabometyx for:

• Renal cell carcinoma

Who Is Running the Clinical Trial?

University of Utah

Lead Sponsor

Trials

1,169

Recruited

1,623,000+

Exelixis

Industry Sponsor

Trials

126

Recruited

20,500+

Michael M. Morrissey

Exelixis

Chief Executive Officer since 2010

PhD in Chemistry from Harvard University, BSc in Chemistry from the University of Wisconsin

Vicki L. Goodman

Exelixis

Chief Medical Officer since 2022

MD

Published Research Related to This Trial

In a meta-analysis of 6 studies involving 201 patients with metastatic castration-resistant prostate cancer, 225Ac-PSMA-617 demonstrated a high efficacy, with 87% of patients showing any decrease in prostate-specific antigen (PSA) levels and 66% achieving a PSA decrease of more than 50%.

The treatment was found to be relatively safe, with the most common side effect being xerostomia (dry mouth) occurring in 77.1% of patients, but only 3% experiencing severe cases, indicating that 225Ac-PSMA-617 is a promising option with manageable toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of 225Ac-PSMA-617-Targeted Alpha Therapy in Metastatic Castration-Resistant Prostate Cancer: A Systematic Review and Meta-Analysis. Ma, J., Li, L., Liao, T., et al.[2022]

177Lu-PSMA-617 is a promising new treatment for patients with advanced prostate cancer, specifically targeting the prostate-specific membrane antigen (PSMA) found on cancer cells.

The therapy was also experimentally applied to a female patient with metastasized leiomyosarcoma, suggesting potential for PSMA-targeted treatment in other types of tumors beyond prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Experimental 177Lu-PSMA-617 radioligand therapy in a patient with extended metastasized leiomyosarcoma. Jüptner, M., Marx, M., Zuhayra, M., et al.[2021]

177Lu-PSMA-617 therapy resulted in a significant decline in PSA levels in 69.30% of patients after the first treatment cycle, indicating its efficacy in treating metastatic castration-resistant prostate cancer (mCRPC).

The therapy was found to be safe, with no significant adverse events reported across 12 studies involving 508 cases, suggesting it is a well-tolerated treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy and safety of the 177Lu-PSMA-617 therapy in the treatment of metastatic castration-resistant prostate cancer: A meta-analysis]. Zhang, H., Xin, P., Zhang, YX.[2022]

In a phase II trial, the novel radiopharmaceutical 177Lu-PSMA-617 demonstrated a significantly higher prostate-specific antigen (PSA) response in men with metastatic castration-resistant prostate cancer, with 66% of patients showing a response compared to only 37% in those treated with chemotherapy (cabazitaxel).

This suggests that 177Lu-PSMA-617 may be a more effective treatment option than traditional chemotherapy for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radionuclide Reduces PSA in mCRPC. [2021]

In a preliminary study of 21 patients with de novo metastatic hormone-sensitive prostate carcinoma (mHSPC) who refused standard treatments, 225Ac-PSMA-617 showed a significant anti-tumor effect, with 95% of patients experiencing a decline in prostate-specific antigen (PSA) levels, and 86% achieving a decline of 50% or more.

The treatment was well tolerated, with the most common side effect being mild dry mouth in 94% of patients, suggesting that 225Ac-PSMA-617 could be a promising alternative therapy for mHSPC patients who decline standard treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

225Ac-PSMA-617 radioligand therapy of de novo metastatic hormone-sensitive prostate carcinoma (mHSPC): preliminary clinical findings. Sathekge, M., Bruchertseifer, F., Vorster, M., et al.[2023]

In a phase 2 trial involving 200 men with metastatic castration-resistant prostate cancer, [177Lu]Lu-PSMA-617 showed a significantly higher prostate-specific antigen (PSA) response rate (66%) compared to cabazitaxel (37%), indicating its greater efficacy as a treatment option.

Patients receiving [177Lu]Lu-PSMA-617 experienced fewer severe adverse events (33%) compared to those on cabazitaxel (53%), suggesting a better safety profile for the radiolabeled therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. Hofman, MS., Emmett, L., Sandhu, S., et al.[2023]

The TheraP trial is a phase 2 study comparing the safety and efficacy of cabazitaxel chemotherapy with 177 Lu-PSMA-617 in men with metastatic castration-resistant prostate cancer (mCRPC) who have previously received docetaxel, involving 200 patients.

177 Lu-PSMA-617 is being evaluated as a potentially life-prolonging treatment option, with the trial aiming to provide the first randomized evidence on its effectiveness compared to cabazitaxel.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TheraP: a randomized phase 2 trial of 177 Lu-PSMA-617 theranostic treatment vs cabazitaxel in progressive metastatic castration-resistant prostate cancer (Clinical Trial Protocol ANZUP 1603). Hofman, MS., Emmett, L., Violet, J., et al.[2021]

Citations

1. nejm.org nejm.org/doi/full/10.1056/NEJMoa2107322

Lutetium-177–PSMA-617 for Metastatic Castration ... This radioligand therapy has been associated with encouraging biochemical and radiographic response rates, reduced pain, and low toxicity in multiple early- ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40752988/

Outcomes for [ 177 Lu]Lu-PSMA-617 with and Without ... Key findings and limitations: Among 256 patients, 106 (41.4%) received an ARPI with [177Lu]Lu-PSMA-617. Those receiving an ARPI had lower ...

3. jnm.snmjournals.org jnm.snmjournals.org/content/66/supplement_1/251923

Outcomes of [177Lu] Lu-PSMA-617 Re-Treatment in ... A favorable imaging response was observed in 10 patients (50%, 10/20), with 4 achieving a complete response and 6 achieving a partial response, ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.5_suppl.112

Outcomes for 177Lu-PSMA-617 with and without ... Patients receiving an ARPI with 177 Lu-PSMA-617 were more likely to complete all 6 cycles of treatment, but no clear differences in survival were observed on ...

5. thelancet.com thelancet.com/journals/lancet/article/PIIS0140-6736(24)01653-2/abstract

177Lu-PSMA-617 versus a change of androgen receptor ... The incidence of grade 3–5 adverse events was lower in the 177Lu-PSMA-617 group (at least one event in 81 [36%] of 227 patients; four [2%] grade ...

6. annalsofoncology.org annalsofoncology.org/article/S0923-7534(25)00852-X/fulltext

Final overall survival and safety analyses of the phase III ... At the time of the final OS analysis, 299 deaths were reported in 142/234 participants (60.7%) in the 177Lu-PSMA-617 arm and 157/234 (67.1%) in ...

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.5_suppl.TPS294

Long-term safety outcomes of 177Lu-PSMA-617 in patients ... The secondary endpoint is the number and proportion of deaths. Following enrollment, patients will undergo assessments at baseline, and then ...

8. urotoday.com urotoday.com/conference-highlights/asco-gu-2025/asco-gu-2025-prostate-cancer/158427-asco-gu-2025-outcomes-for-177lu-psma-617-with-and-without-concurrent-use-of-androgen-receptor-pathway-inhibitors-in-patients-with-mcrpc.html

ASCO GU 2025: Outcomes for 177Lu-PSMA-617 with and ... Median overall survival for the overall cohort was 21.3 (95% CI 16.7 – 25.9) months and significantly longer for those receiving androgen receptor pathway ...