ALA + Radiation for Solid Cancers

Overseen By Anthony Olszanski, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Fox Chase Cancer Center

Must not be taking: Steroids, Intravenous antibiotics

Disqualifiers: Symptomatic brain metastases, Active infections, others

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

Compensation: Varies

Number of Visits: Unknown

130 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a phase 1, open label, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study to determine the maximum tolerated doses (MTD) or recommended phase 2 doses (RP2D) of both ALA and RT. Once the MTDs are identified, the cohort providing the highest dose intensity at or below the MTD (if supported by emerging PK and biomarker data) will be selected for an expansion phase for the purpose of refining the safety assessment and assessing preliminary efficacy. The initial dose escalation phase will enroll at least 20 patients across a variety of tumor types, after which concurrent disease site-specific expansion cohorts will accrue, each consisting of 20 patients. Anatomic site-specific cohorts will include patients with symptomatic metastatic disease to specific anatomic regions, where varying toxicity may be expected (Head and Neck, Thorax and Abdomen/Pelvis).

Will I have to stop taking my current medications?

The trial requires that all previous cancer therapies, including radiotherapy, major surgery, and investigational therapies, must be stopped for at least 14 days before starting the trial treatment. However, the protocol does not specify about other non-cancer medications, so it's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the treatment ALA + Radiation for Solid Cancers?

The research does not directly address the effectiveness of ALA (5-aminolevulinic acid) combined with radiation for solid cancers, but similar combination therapies, like 5-fluorouracil with radiation, have shown enhanced antitumor effects in other studies. ^{1 2 3 4 5}

Is 5-aminolevulinic acid (5-ALA) safe for use in humans?

5-aminolevulinic acid (5-ALA) is generally considered safe for use in humans, as it has been approved by the European Medicines Agency for treating actinic keratosis, a skin condition. The most common side effects are reactions at the site of application, such as redness or irritation. ^{6 7 8 9 10}

How does the ALA + Radiation treatment differ from other cancer treatments?

The ALA + Radiation treatment is unique because it combines 5-aminolevulinic acid (a compound that makes cancer cells more sensitive to light) with low-dose radiation, potentially enhancing the effectiveness of radiation therapy. This approach may offer a novel way to target solid tumors, especially in cases where traditional treatments are less effective. ^{11 12 13 14 15}

Eligibility Criteria

Adults with advanced solid tumors resistant to standard treatments or without available standard therapies can join this trial. They must be able to undergo PET/MRI imaging, have stable vital signs and organ function, and not have had recent cancer treatments. Women of childbearing potential and men must agree to use contraception.

Inclusion Criteria

I am a woman who cannot become pregnant or will use birth control during and after the trial.

I am willing to undergo MRI imaging.

I have not been treated with bleomycin before radiation to my chest.

Exclusion Criteria

Patients with implanted battery-controlled devices (including, but not limited to, pacemakers and implanted cardiovascular defibrillator (AICDs)) that may suffer interference from neutron contamination of high energy photon beams

Pregnant or breast-feeding patients

I have HIV/AIDS but haven't been tested for this study.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive 3 doses of ALA and fractions of radiation therapy during a 21-day cycle to determine the maximum tolerated dose (MTD)

3 weeks

Multiple visits (in-person)

Expansion

Cohorts are expanded to refine safety assessment and assess preliminary efficacy

56 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

Treatment Details

Interventions

• 5-aminolevulinic Acid
• Low dose radiation

Trial Overview The study is testing the safety and effectiveness of combining low dose radiation (RT) with a drug called ALA in escalating doses. It aims to find the highest dose patients can tolerate without severe side effects, then expand the trial for further safety evaluation and preliminary efficacy results.

Participant Groups

Group I: ALA / Fractions of Radiotherapy Experimental Treatment 1 Intervention

Subjects will receive 3 doses of ALA and fractions of radiation therapy during the course of one 21day cycle. Only one cycle per patient is allowed.

5-aminolevulinic Acid is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Levulan for:

• Actinic keratoses of the face and scalp
• Visualization of glioma during surgery

Approved in European Union as Ameluz for:

• Actinic keratoses of the face and scalp
• Field-directed treatment of actinic keratoses of mild-to-moderate severity on the face and scalp

Approved in Canada as 5-Aminolevulinic acid for:

• Actinic keratoses of the face and scalp
• Visualization of glioma during surgery

Who Is Running the Clinical Trial?

Fox Chase Cancer Center

Lead Sponsor

Trials

236

Recruited

39,300+

Findings from Research

The FAR therapy, a combination of 5-fluorouracil, vitamin A, and external radiation, was successfully administered to 95 patients with T2N0 glottic carcinoma, with 98% completing the treatment course.

This approach achieved a high local control rate of 91% and a 5-year disease-specific survival rate of 97%, while preserving laryngeal function in 91% of patients, indicating its efficacy and safety for this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

"FAR" chemoradiotherapy improves laryngeal preservation rates in patients with T2N0 glottic carcinoma. Kumamoto, Y., Masuda, M., Kuratomi, Y., et al.[2013]

The combination of 5-fluorouracil (5-FU) and vitamin A significantly enhances the drug's ability to inhibit RNA formation and increases cellular sensitivity to radiation, making it more effective than 5-FU alone.

In a clinical study involving 275 patients with various head and neck cancers treated with the FAR therapy (5-FU, vitamin A, and cobalt-60 radiation) from 1972 to 1977, the treatment demonstrated highly effective synergism, suggesting a promising approach for cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synergistic combination therapy of 5-fluorouracil, vitamin A, and cobalt-60 radiation for head and neck tumors--antitumor combination therapy with vitamin A. Komiyama, S., Kudoh, S., Yanagita, T., et al.[2019]

Cisplatin, when used as a radiosensitizer in conjunction with radiation therapy for advanced squamous cell carcinoma of the head and neck, has shown to significantly improve treatment outcomes, including higher response rates and prolonged survival.

The mechanism of action for cisplatin's effectiveness includes its ability to enhance DNA damage in tumor cells and inhibit their repair, which leads to better control of the disease when combined with radiation therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiosensitization of advanced squamous cell carcinoma of the head and neck with cisplatin during concomitant radiation therapy. Sharma, VM., Wilson, WR.[2019]

In a Phase I study involving 27 patients with locally advanced pancreatic or biliary carcinoma, significant toxicities were observed, with 8 patients experiencing severe side effects such as nausea, vomiting, and myelosuppression, indicating that the treatment regimen may be poorly tolerated.

The study suggests that older patients (over 70 years) and those with a lower performance status are at higher risk for severe toxicities, leading to a recommendation to limit the dose of 5-fluorouracil to 350 mg/m2/day to improve safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of combined radiation therapy with 5-fluorouracil and low dose folinic acid in patients with locally advanced pancreatic or biliary carcinoma. Hsue, V., Wong, CS., Moore, M., et al.[2019]

The study found that the prodrug 5'-deoxy-5-fluorouridine (5'-DFUR) combined with radiotherapy produced more than additive antitumor effects against colon cancer in mice, especially with fractionated doses, compared to the standard chemotherapy drug 5-fluorouracil (5-FU) which only showed additive effects.

5'-DFUR demonstrated a better safety profile, causing less damage to normal tissues compared to 5-FU, which resulted in significant toxicity; this suggests that 5'-DFUR may be a more effective and safer option for cancer treatment in combination with radiation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative antitumor activity of 5-fluorouracil and 5'-deoxy-5-fluorouridine in combination with radiation therapy in mice bearing colon 26 adenocarcinoma. Ishikawa, T., Tanaka, Y., Ishitsuka, H., et al.[2019]

In a study involving mice with human colon cancer, administration of 5-aminolevulinic acid (5-ALA) before X-ray irradiation significantly reduced tumor volume compared to mice that did not receive 5-ALA, indicating its potential as a radiosensitizer.

The results showed that multiple irradiations combined with 5-ALA treatment effectively inhibited tumor growth, suggesting that 5-ALA enhances the effectiveness of radiation therapy in colon cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Radiosensitizing effect of 5-aminolevulinic acid (5-ALA ) in Colon cancer]. Kamada, Y., Murayama, Y., Harada, K., et al.[2015]

5-aminolaevulinic acid (ALA) shows promise as a photosensitizer for photodynamic therapy (PDT) in cancer, with significant localization in the perinuclear cytoplasm and nucleus of CPAE and PTK2 cells, indicating targeted areas for treatment.

Subcellular phototoxicity studies revealed that the nucleus and perinuclear regions are the most sensitive to ALA-induced damage, while the peripheral cytoplasm showed minimal sensitivity, suggesting a strategic approach for maximizing therapeutic effects while minimizing damage to healthy cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Subcellular phototoxicity of 5-aminolaevulinic acid (ALA). Liang, H., Shin, DS., Lee, YE., et al.[2019]

5-aminolaevulinic acid (Ameluz) has been authorized for use in the European Union to treat mild to moderate actinic keratosis on the face and scalp, based on its effectiveness in improving the complete response rate of lesions.

The treatment involves applying the gel to the lesions and surrounding area, followed by illumination with red light, which activates a compound that destroys the target cells; common side effects include local reactions at the application site.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The European Medicines Agency approval of 5-aminolaevulinic acid (Ameluz) for the treatment of actinic keratosis of mild to moderate intensity on the face and scalp: summary of the scientific assessment of the Committee for Medicinal Products for Human Use. Tzogani, K., Straube, M., Hoppe, U., et al.[2018]

5-Aminolevulinic acid (ALA) enhances the accumulation of protoporphyrin IX (PpIX) in tumor cells, which increases the generation of reactive oxygen species (ROS) when combined with X-ray irradiation, leading to improved tumor cell death.

In a study involving mouse B16-BL6 melanoma cells, local administration of 50 mg/kg ALA before fractionated radiation therapy significantly improved tumor suppression, suggesting that ALA could enhance the effectiveness of cancer radiotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

5-Aminolevulinic acid enhances cancer radiotherapy in a mouse tumor model. Takahashi, J., Misawa, M., Murakami, M., et al.[2021]

5-aminolaevulinic acid (ALA) effectively induces porphyrin photosensitization for photodynamic therapy (PDT) in pancreatic cancer, with the highest sensitization achieved through intravenous administration of 200 mg/kg ALA.

PDT using laser light resulted in significant tumor necrosis and improved survival in treated Syrian golden hamsters compared to untreated controls, indicating potential for ALA-PDT in treating pancreatic tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Photodynamic therapy using 5-aminolaevulinic acid for experimental pancreatic cancer--prolonged animal survival. Regula, J., Ravi, B., Bedwell, J., et al.[2019]

Low doses of alpha radiation (1.36 and 6.8 cGy) can stimulate the proliferation of human lung adenocarcinoma (A549) cells, while higher doses (13.6-54.4 cGy) are cytotoxic, indicating a dose-dependent response.

In vivo studies showed that A549 cells exposed to low doses of alpha radiation resulted in significantly larger tumor volumes in SCID mice, suggesting that low-dose alpha radiation may promote tumor growth rather than inhibit it.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cytoproliferative effect of low dose alpha radiation in human lung cancer cells is associated with connexin 43, caveolin-1, and survivin pathway. Rajan, V., Pandey, BN.[2021]

The study found that (213)Bi immunoconjugates can effectively kill both hypoxic and normoxic CAL33 tumor cells, demonstrating their potential as a treatment for tumors that are resistant to conventional therapies due to low oxygen levels.

Unlike traditional photon radiation, which is less effective on hypoxic cells, the α-particle emitting (213)Bi showed consistent efficacy regardless of the oxygenation status of the tumor cells, making it a promising strategy for targeting hypoxic tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alpha-particle emitting 213Bi-anti-EGFR immunoconjugates eradicate tumor cells independent of oxygenation. Wulbrand, C., Seidl, C., Gaertner, FC., et al.[2021]

The study demonstrated that Diffusing Alpha-emitters Radiation Therapy (DART) effectively retards tumor growth and can lead to tumor eradication in solid squamous cell carcinoma (SCC) tumors in mice, using alpha-emitting radioisotopes from (224)Ra.

DART showed enhanced efficacy when applied to smaller tumors or when using multiple DART wires, suggesting a promising approach for cancer treatment that could be combined with other therapies like chemotherapy or immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Growth retardation and destruction of experimental squamous cell carcinoma by interstitial radioactive wires releasing diffusing alpha-emitting atoms. Cooks, T., Arazi, L., Schmidt, M., et al.[2016]

Using a dual delivery strategy for α-particle emitters in prostate cancer treatment significantly improves tumor growth inhibition compared to using a single delivery method, as shown in a mouse model.

This approach allows for more uniform irradiation of tumors, effectively targeting both avascular and perivascular regions, which may enhance the efficacy of α-particle radiotherapies for established tumors that are difficult to treat.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two diverse carriers are better than one: A case study in α-particle therapy for prostate specific membrane antigen-expressing prostate cancers. Salerno, D., Howe, A., Bhatavdekar, O., et al.[2022]

In a study involving 28 patients with locally advanced and recurrent squamous cancers, the novel alpha-emitter radiation therapy (DaRT) demonstrated a high complete response rate of 78.6% for treated lesions, indicating its efficacy in tumor reduction.

The treatment was associated with manageable acute toxicities, primarily local pain and mild skin ulceration, with no severe grade 3 or higher toxicities reported, suggesting a favorable safety profile for this innovative therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Initial Safety and Tumor Control Results From a "First-in-Human" Multicenter Prospective Trial Evaluating a Novel Alpha-Emitting Radionuclide for the Treatment of Locally Advanced Recurrent Squamous Cell Carcinomas of the Skin and Head and Neck. Popovtzer, A., Rosenfeld, E., Mizrachi, A., et al.[2020]

References

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

"FAR" chemoradiotherapy improves laryngeal preservation rates in patients with T2N0 glottic carcinoma. [2013]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Synergistic combination therapy of 5-fluorouracil, vitamin A, and cobalt-60 radiation for head and neck tumors--antitumor combination therapy with vitamin A. [2019]

3. Germany pubmed.ncbi.nlm.nih.gov

Radiosensitization of advanced squamous cell carcinoma of the head and neck with cisplatin during concomitant radiation therapy. [2019]

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

A phase I study of combined radiation therapy with 5-fluorouracil and low dose folinic acid in patients with locally advanced pancreatic or biliary carcinoma. [2019]

5. Japan pubmed.ncbi.nlm.nih.gov

Comparative antitumor activity of 5-fluorouracil and 5'-deoxy-5-fluorouridine in combination with radiation therapy in mice bearing colon 26 adenocarcinoma. [2019]

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

[Radiosensitizing effect of 5-aminolevulinic acid (5-ALA ) in Colon cancer]. [2015]

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

Subcellular phototoxicity of 5-aminolaevulinic acid (ALA). [2019]

8. England pubmed.ncbi.nlm.nih.gov

The European Medicines Agency approval of 5-aminolaevulinic acid (Ameluz) for the treatment of actinic keratosis of mild to moderate intensity on the face and scalp: summary of the scientific assessment of the Committee for Medicinal Products for Human Use. [2018]

9. Switzerland pubmed.ncbi.nlm.nih.gov

5-Aminolevulinic acid enhances cancer radiotherapy in a mouse tumor model. [2021]

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

Photodynamic therapy using 5-aminolaevulinic acid for experimental pancreatic cancer--prolonged animal survival. [2019]

11. England pubmed.ncbi.nlm.nih.gov

Cytoproliferative effect of low dose alpha radiation in human lung cancer cells is associated with connexin 43, caveolin-1, and survivin pathway. [2021]

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

Alpha-particle emitting 213Bi-anti-EGFR immunoconjugates eradicate tumor cells independent of oxygenation. [2021]

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

Growth retardation and destruction of experimental squamous cell carcinoma by interstitial radioactive wires releasing diffusing alpha-emitting atoms. [2016]

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

Two diverse carriers are better than one: A case study in α-particle therapy for prostate specific membrane antigen-expressing prostate cancers. [2022]

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

Initial Safety and Tumor Control Results From a "First-in-Human" Multicenter Prospective Trial Evaluating a Novel Alpha-Emitting Radionuclide for the Treatment of Locally Advanced Recurrent Squamous Cell Carcinomas of the Skin and Head and Neck. [2020]