Advanced Cancer, Breast Cancer, Cancer, Cervical Cancer, Colorectal Cancer, Diffuse Midline Glioma, H3 K27M-Mutant, DIPG Brain Tumor, Endometrial Cancer, Esophageal Cancer, Gastric Cancer, Glioma, Malignant, Head and Neck Cancer, Melanoma, Mesothelioma Peritoneum, Mesotheliomas Pleural, Nsclc, Ovary Cancer, Papillary Thyroid Cancer, Solid Carcinoma, Solid Tumor
Conditions
Keywords
DFMO IV, AMXT 1501, DFMO
Brief summary
A Phase 1B/2A study will be conducted to establish safety and dose level of AMXT 1501 dicaprate in combination with IV DFMO, in cancer patients.
Detailed description
The objective of this study is to determine the safety and tolerability of oral AMXT 1501 dicaprate (AMXT1501) in combination with IV DFMO in patients with advanced solid tumors, or DIPG/DMG. Secondary objectives include characterization of plasma pharmacokinetics (PK), pharmacodynamic (PD), and other biomarker efficacy assessments of the impact of AMXT 1501 in combination with IV DFMO on polyamine uptake by circulating lymphocytes (blood cells). To these aims, the study will evaluate the safety, PK, PD, and other biomarker efficacy profiles of orally-administered AMXT 1501 and IV DFMO. Approximately, 56 patients will be enrolled to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of AMXT 1501 and IV DFMO in combination. The MTD is defined as the highest dose level below at which dose escalation is stopped.
Interventions
Sponsors
Aminex Therapeutics, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* IMPORTANT NOTE- Younger 12-17 year old patients are also eligible for this study if they meet the noted DIPG or DMG criteria noted below, which is separate from Patient Diagnosed with Advanced Solid Tumors. * Patients will be eligible for study participation only if they meet ALL the inclusion criteria applicable to their diagnosis. INCLUSION FOR PATIENTS DIAGNOSED WITH ADVANCED SOLID TUMORS * Understand and sign written IRB-approved informed consent form and be willing to comply with all study procedures. * Diagnosed with unresectable, locally advanced, or metastatic solid tumor for which no standard therapy is recognized or for which standard therapy has failed. Planned tumor types for evaluation include: * Platinum resistant ovarian cancer (including - primary peritoneal cancer and fallopian tube cancer) * Breast cancer * Papillary thyroid cancer * Head and neck cancer * Gastric cancer * Non-small cell lung cancer (NSCLC) * Mesothelioma: Pleural and peritoneal * Esophageal * Endometrial cancer * Cervical * Melanoma * Colorectal cancers (colon, rectal) * Grade 4 Gliomas (including both IDH WT and IDH-mutant astrocytoma) * Must be ≥18 years of age. * Histologically or cytologically documented disease. * Has evaluable or measurable disease by RECIST v1.1 or mRECIST criteria. o For patients with Grade 4 glioma, has evaluable or measurable disease by RANO (Appendix 5). * Provide tumor tissue from biopsy taken during Screening period. * Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale. INCLUSION FOR PATIENTS DIAGNOSED WITH DIPG OR DMG Patients must also meet other generally noted criteria as noted within the protocol * For patients \<18 years of age, the parents or legal guardians must understand and sign the written IRB-approved informed consent form (ICF). The patient, if able, must understand and sign the IRB-approved consent (assent) and be willing to comply with all study procedures. o For patients ≥18 years of age, the patient must understand and sign written IRB-approved ICF and be willing to comply with all study procedures. * Diagnosed with DIPG or DMG. o Any anatomic site of origin is acceptable. * Must be ≥12 years of age and \>40 kg in body weight. * Radiologically documented disease. * (a) - Patient with refractory or progressive DIPG or DMG, defined as tumors with a pontine epicenter and diffuse involvement of at least 2/3 of the pons, are eligible without histologic confirmation. * (b) - Patients with brainstem tumors that do not meet radiographic criteria or are not considered to be typical DIPG or DMG will be eligible if the tumors have been biopsied and proven to be high-grade gliomas (such as anaplastic astrocytoma, glioblastoma, H3 K27M-mutant DMG). * Has evaluable or measurable disease by RANO or RAPNO criteria. o Has evaluable or measurable disease by RANO (for adults) or RAPNO (for children * Provide cerebrospinal fluid (CSF) sample. Patients with pontine lesions for whom a radiological diagnosis of DIPG, or DMG is made will be eligible without a CSF sample, although CSF sample is strongly encouraged. * Performance score: * (a) Patients \>16 years of age, Karnofsky score ≥50%. * (b) Patients ≥12 and ≤16 years of age, Lansky ≥50%. Note: Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score. INCLUSION FOR ALL PATIENTS All patients are required to meet these inclusion
Exclusion criteria
to be considered eligible for the study * Patients must have fully recovered from the acute toxic effects of all prior anti-cancer chemotherapy: The following minimum periods from treatment apply: * (a) Myelosuppressive chemotherapy: At least 21 days after the last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea). * (b) Hematopoietic growth factors: At least 14 days after the last dose of a long-acting growth factor (e.g., Neulasta) or 7 days for short-acting growth factor. * (c) Biologic (anti-neoplastic agent): At least 7 days after the last dose of a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. * (d) Immunotherapy: At least 42 days after the completion of any type of vaccination. * (e) Monoclonal antibodies: \>21 days must have elapsed from the infusion of last dose of antibody and toxicity related to antibody therapy must be recovered to Grade ≤1. * (f) Radiation therapy: Patients must have had their last fraction of craniospinal or focal irradiation a minimum of 8-12 weeks prior to enrollment. * (g) Stem cell transplant: Patients must be ≥3 months since autologous stem cell transplant. Patients who received allogenic stem cell transplant or solid organ transplant are not eligible for study. * Patient is able to take oral medications and willing to use an at-home infusion pump. * Must have adequate bone marrow and renal/hepatic function at the screening and baseline visits, defined as: * (a) Absolute neutrophil count (ANC) ≥1.5×109/L without granulocyte colony-stimulating factor (G-CSF) support within 7 days * (b) Platelet ≥100×109/L, without transfusion within 7 days * (c) Hemoglobin ≥9 g/dL, without transfusion support within 7 days * (d) Activated partial thromboplastin time/ partial thromboplastin time (aPTT/PTT) ≤1.5×ULN. * (e) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5×ULN (if liver metastases are present, then ≤5×ULN is allowed). * (f) Total serum bilirubin ≤1.5×ULN, (except for patients with known Gilbert's Syndrome in whom ≤3×ULN is permitted). * (g) The patient is clinically euthyroid. * (h) Renal: Serum creatinine \<1.5×ULN or creatinine clearance ≥60 mL/min/1.73 m2 for patients with serum creatinine levels \>1.5×ULN. * (i) Any Grade 3 or higher lab abnormalities should be discussed and approved by the Medical Monitor prior to enrollment (even if not considered clinically significant). * Active secondary malignancies will not be allowed, with the exception of: * (a) Adequately treated basal cell carcinoma, SCC of the skin, or in situ cervical cancer; * (b) Adequately treated Stage 1 cancer from which the subject is currently in remission and has been in remission for ≥2 years; * (c) Low-risk prostate cancer with Gleason score \<7 and prostate-specific antigen \<10 ng/mL, or * (d) Any other cancer from which the patient has been disease-free for ≥3 years. * Patient compliance and geographic proximity (as determined by the Principal Investigator \[PI\]) to allow adequate follow-up. * Both male and female patients must be willing to consent to using highly effective contraception prior to study entry, while on treatment, and at least 3 months thereafter
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Determine safety and tolerability of AMXT1501 in combination with IV DFMO | 1 year | To evaluate the safety and tolerability of AMXT1501 and IV DFMO combination in patients through collecting the number of patients with Treatment Related Adverse Events that occur in patients from first dose, AEs assessed by CTCAEv5.0 |
| Determine DLTs and RP2Ds in AMXT 1501 in combination with IV DFMO | 1 year | Indicate Number of patients with DLTs in AMXT1501 in combination with IV DFMO in patients with advanced cancer to determine the RP2D within the duration of the dose escalation period of the study as defined by the DLT definition of the protocol from baseline to end of Cycle 1 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Determine the PK using Cmax of AMXT 1501 and IV DFMO | 6 months | To evaluate the pharmacokinetics (PK) of AMXT 1501 and IV DFMO |
| Characterize investigator defined response Overall Response Rate (ORR) using RECIST v1.1 | 6 months | To characterize Investigator defined Overall Response Rate (ORR) using RECIST v1.1 response criteria. |
| Characterize AMXT1501 and IV DFMO on the expression of immune related gene signatures | 1 year | Evaluate the effects of AMXT1501 and IV DFMO on the expression of immune related gene signatures, immune cell phenotype by IHC, AMXT1501 and DFMO drug levels impact on polyamine levels |
| Characterize investigator defined Duration of Response (DOR) | 6 months | To characterize Investigator defined Duration of Response (DOR), using RECIST v1.1 response criteria and length of time (in days) from last study drug administration to time patient has progressive disease. |
| Determine the PK using AUC of AMXT 1501 and IV DFMO | 6 months | To evaluate the pharmacokinetics (PK) of AMXT 1501 in combination with IV DFMO in patients |
Other
| Measure | Time frame | Description |
|---|---|---|
| Evaluate AMXT1501 and DFMO on PD biomarker by evaluating the level/concentration of polyamine uptake. | 6 months | Will evaluate the effect of AMXT1501 and DFMO on pharmacodynamic (PD) biomarker of polyamine uptake in the blood starting at Cycle 1 through the end of Cycle 2 and again at the beginning of each new cycle. |
Countries
Australia, United States
Outcome results
None listed