What is the mechanism of action of this treatment?

Common treatments for Isocitrate Dehydrogenase (IDH) mutations include All-Trans Retinoic Acid (ATRA) and PD-1 inhibitors like Retifanlimab. ATRA works by inducing differentiation and apoptosis in cancer cells, thereby reducing their proliferation. PD-1 inhibitors enhance the immune response by blocking the PD-1 pathway, which cancer cells use to evade immune detection. These treatments are significant for IDH-mutant patients as they directly target cancer cells and boost the body's immune system to combat the tumor more effectively.

What side effects are associated with this type of intervention?

Common side effects of All-Trans Retinoic Acid (ATRA) include headache, fever, dry skin, and elevated liver enzymes. PD-1 inhibitors like Retifanlimab can cause immune-related adverse events such as fatigue, rash, diarrhea, and more severe conditions like pneumonitis, colitis, hepatitis, and endocrinopathies. Combining these treatments may result in overlapping toxicities, requiring careful monitoring.

What prior FDA approvals exist?

The FDA has approved several treatments targeting IDH mutations, particularly in gliomas and acute myeloid leukemia (AML). For instance, Ivosidenib (Tibsovo) and Enasidenib (Idhifa) are approved for IDH1 and IDH2 mutations in AML, respectively. These drugs work by inhibiting the mutant IDH enzymes, leading to differentiation and apoptosis of cancer cells. While these treatments do not directly align with the combination of ATRA and PD-1 inhibitors like Retifanlimab, they share the goal of targeting specific mutations to induce cancer cell differentiation and death. PD-1 inhibitors such as Pembrolizumab and Nivolumab are also FDA-approved for various cancers, enhancing the immune response against tumors, similar to Retifanlimab's mechanism.

What other types of research exist?

Promising novel alternatives for treating IDH-mutant patients in 2024 include: 1) IDH inhibitors such as Ivosidenib (IDH1 inhibitor) and Enasidenib (IDH2 inhibitor), which target the mutant IDH enzyme directly. 2) ONC201, a selective DRD2 antagonist, which has shown efficacy in IDH-mutant gliomas. 3) Combination therapies involving hypomethylating agents like CC-486 with immune checkpoint inhibitors such as Durvalumab, which may enhance anti-tumor immune responses. These alternatives have shown potential in clinical trials and could be considered for treatment in 2024.

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ATRA + PD-1 Inhibitor for Brain Tumor

Phase 2

Recruiting

Led By Stephen Bagley, MD MSCE

Research Sponsored by Stephen Bagley, MD, MSCE

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Age 18 or older

Karnofsky performance status greater than or equal to 60

Must not have

Known active hepatitis B virus (HBsAg reactive) or active hepatitis C virus (HCV RNA detectable by PCR)

Active autoimmune disease requiring systemic immunosuppression in excess of physiologic maintenance doses of corticosteroids

Timeline

Screening 3 weeks

Treatment Varies

Follow Up 84 months

Awards & highlights

No Placebo-Only Group

Summary

This trial tests a combination of a vitamin A derivative and an immune-boosting drug in patients with recurring brain tumors. The treatment aims to normalize cancer cell behavior and enhance the immune system's ability to fight the tumor.

Who is the study for?

Adults with recurrent brain tumors (astrocytoma or oligodendroglioma) that have IDH mutations and have tried at least one chemo treatment can join. They must be able to perform daily activities, not pregnant, agree to contraception, and understand the study. Excluded are those with allergies to trial drugs, other serious illnesses, recent bevacizumab treatment, significant mass effect on the brain or active infections.

What is being tested?

The trial tests a combination of All-Trans Retinoic Acid (ATRA) and PD-1 inhibitor Retifanlimab in patients with specific recurrent brain tumors. It aims to see if this mix is safe and boosts the immune system's ability to fight cancer.

What are the potential side effects?

Possible side effects include allergic reactions to ATRA or Retifanlimab components, increased risk of infection due to immune suppression from treatments, lung issues like pneumonitis or interstitial lung disease, and potential autoimmune responses.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I am 18 years old or older.

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I can care for myself but may not be able to do active work.

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I have a confirmed diagnosis of astrocytoma or oligodendroglioma that has worsened or returned after chemotherapy.

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I haven't used 5-ALA for surgery because it reacts with my ATRA treatment.

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I understand the study and agree to participate by signing the consent form.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I have active hepatitis B or C.

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I am taking high doses of steroids for an autoimmune disease.

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I have not taken bevacizumab in the last 3 months.

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My cancer has spread to the lining of my brain and spinal cord.

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I have serious heart problems that are not under control.

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I have or had lung scarring or inflammation not caused by an infection.

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I have a tumor in my brainstem or spinal cord that shows up on scans, but I don't have a known tumor in my spinal cord.

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I do not have another cancer that could affect this trial's safety or results.

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I am allergic to tretinoin or similar medications.

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I am HIV-positive and currently on antiretroviral therapy.

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I have a significant brain swelling or shift.

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I had severe side effects from previous immunotherapy that required stopping the treatment.

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I am not allergic to retifanlimab or its ingredients.

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I have had a solid organ or bone marrow transplant.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ 84 months

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~84 months

This trial's timeline: 3 weeks for screening, Varies for treatment, and 84 months for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Objective radiographic response (ORR)

Secondary study objectives

Incidence of Treatment-Emergent Adverse Events as assessed by NCI CTCAE v 5.0

Overall survival

Progression Free Survival

Side effects data

From 2021 Phase 2 trial • 94 Patients • NCT03597295

23%

Asthenia

21%

Diarrhoea

18%

Fatigue

16%

Nausea

16%

Anaemia

15%

Vomiting

13%

Constipation

13%

Decreased appetite

12%

Pruritus

12%

Cough

12%

Dyspnoea

11%

Pyrexia

10%

Hypothyroidism

10%

Rectal haemorrhage

Arthralgia

Back pain

Headache

Weight decreased

Urinary tract infection

Proctalgia

Aspartate aminotransferase increased

Abdominal pain

Insomnia

Hypokalaemia

Rash

Cystitis

General physical health deterioration

Pelvic pain

Hypercalcaemia

Inadequate analgesia

Intestinal obstruction

Haematuria

Pleural effusion

Sepsis

Pneumonia

Purpura

Mental status changes

Respiratory failure

Proctitis haemorrhagic

Pseudomonas infection

Acute kidney injury

Anal abscess

Gastroenteritis

Interstitial lung disease

Pancreatic carcinoma

Adrenal insufficiency

Hydronephrosis

Ileus

Flank pain

Immune-mediated enterocolitis

Large intestinal obstruction

Pain

Acute respiratory failure

Cholecystitis acute

Lyme disease

Lymphangiosis carcinomatosa

Herpes zoster

Hepatitis

Pelvic infection

Peritonitis

Blood bilirubin increased

Body temperature increased

Bone pain

Cellulitis

Cholangitis

Cholecystitis

Cognitive disorder

Colonic fistula

Coma hepatic

Dehydration

Device related infection

Diffuse large B-cell lymphoma

Fall

Femur fracture

Gastric ulcer

Skin infection

Stoma site infection

Superior mesenteric artery syndrome

Thrombosis

Transitional cell carcinoma

Tumour embolism

Tumour pain

Ureteric compression

Urinary retention

Venous thrombosis limb

Pulmonary embolism

Catheter site pain

Pneumocystis jirovecii pneumonia

100%

80%

60%

40%

20%

Study treatment Arm

Retifanlimab 500 mg

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

4Treatment groups

Experimental Treatment

Group I: Arm D (surgical arm, ATRA + retifanlimab pre-operatively)Experimental Treatment2 Interventions

Subject in Arm D will receive the combination of ATRA 45mg/m2/day orally in two equally divided doses for 14 days pre-surgery plus a 500mg IV dose of retifanlimab 14 days prior to the date of surgery. Following surgery all patients will receive 28-day cycles of treatment, with ATRA 45mg/m2/day given orally in two equally divided doses on days 1-14 and retifanlimab 500mg IV on day 1.

Group II: Arm C (surgical arm, ATRA alone pre-operatively)Experimental Treatment2 Interventions

Subject in Arm C will receive ATRA 45mg/m2/day orally in two equally divided doses for 14 days pre-surgery, then undergo surgery. Following surgery all patients will receive 28-day cycles of treatment, with ATRA 45mg/m2/day given orally in two equally divided doses on days 1-14 and retifanlimab 500mg IV on day 1.

Group III: Arm B (failed only one prior alkylating chemotherapy)Experimental Treatment2 Interventions

Subject in Arm B are patients who have failed only one prior alkylating chemotherapy regimen and have gone at least 12 months since the last treatment. Subjects in Arm B will receive 28-day cycles of treatment, with ATRA 45mg/m2/day given orally in two equally divided doses on days 1 through 14 and retifanlimab 500mg IV on day 1.

Group IV: Arm A (failed prior TMZ + one other alkylating chemotherapy)Experimental Treatment2 Interventions

Subjects in Arm A are alkylator-refractory and at high risk for progression of disease, have failed temozolmide and another alkylating agent. Subjects in Arm A will receive 28-day cycles of treatment, with ATRA 45mg/m2/day given orally in two equally divided doses on days 1 through 14 and retifanlimab 500mg IV on day 1.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Retifanlimab

2018

Completed Phase 2

~430

All-trans retinoic acid

2012

Completed Phase 3

~1050

0 / 19Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Common treatments for Isocitrate Dehydrogenase (IDH) mutations include All-Trans Retinoic Acid (ATRA) and PD-1 inhibitors like Retifanlimab. ATRA works by inducing differentiation and apoptosis in cancer cells, thereby reducing their proliferation. PD-1 inhibitors enhance the immune response by blocking the PD-1 pathway, which cancer cells use to evade immune detection. These treatments are significant for IDH-mutant patients as they directly target cancer cells and boost the body's immune system to combat the tumor more effectively.

Photopheresis--extracorporeal irradiation of 8-MOP containing blood--a new therapeutic modality.Co-Therapy of Albendazole and Dexamethasone Reduces Pathological Changes in the Cerebral Parenchyma of Th-1 and Th-2 Dominant Mice Heavily Infected with Angiostrongylus cantonensis: Histopathological and RNA-seq Analyses.An open-label, phase II multicohort study of an oral hypomethylating agent CC-486 and durvalumab in advanced solid tumors.