MTX-531-001 Phase 1 Study in Advanced Solid Tumors

Age

1. Age ≥18 years at the time of signing the informed consent.

   Disease Characteristics

2. Has one of the following types of advanced or refractory solid tumor malignancy:

   EC - No specific requirement

   1. FIGO stage III or IV (unresectable, recurrent, or metastatic disease) at study entry
   2. Received 1, 2, or 3 prior systemic regimens in any setting that must include:

   i. Anti-PD(L)1 in any setting (unless contraindicated) ii. A platinum-containing chemotherapy in any setting c. Adjuvant/neoadjuvant chemotherapy with or without additional anti-cancer therapy will not count as a prior regimen in the absence of recurrence during or within 6 months of completion of the last dose of planned therapy.

   MBC - No specific requirement

   1. Advanced or metastatic disease at the time of entry
   2. HER2 negative according to American Society of Clinical Oncology/College of American Pathologists guidelines, defined as a HER2 IHC score of 0 or 1+, or an IHC score of 2+ accompanied by a negative fluorescence, chromogenic, or silver in situ hybridization test indicating the absence of HER2 gene amplification, or a HER2/CEP17 ratio of \<2.0 based on the most recent tumor biopsy and assessed locally.
   3. Refractory to or relapsed after at 2, 3, 4, or 5, prior systemic regimens for metastatic disease, including (unless contraindicated):

   i. At least 1 cytotoxic chemotherapy regimen (as single agent or combination) in any setting.

   ii. At least 1 anticancer hormonal treatment in any setting. iii. At least 1 cyclin-dependent kinase inhibitor 4/6 in any setting. iv. Other treatments (eg, antibody-drug conjugates, PI3K pathway inhibitors) are allowed as long as the number of prior lines of therapy is not exceeded.

   d. Participants with bone-only metastases are excluded unless antitumor activity can be assessed using elevated baseline clinical tumor markers (eg, CA15-3, CA 27-29, CEA), or ctDNA.

   HNSCC - No specific requirement

   a. Recurrent, locally advanced or metastatic at time of entry b. Received 1, 2, 3, or 4 prior systemic regimens in any setting that must include: i. A platinum-based regimen in the relapse/metastatic setting ii. An anti-PD(L)1 in any setting.

   Advanced or metastatic CRC Pan-RAS and BRAF wildtype in tumor and/or ctDNA

   1. Advanced or metastatic disease at the time of entry
   2. Received 1, 2, 3, or 4 prior systemic regimens for the treatment of advanced or metastatic CRC that must include the following (unless contraindicated):

   i. Fluoropyrimidine ii. Irinotecan iii. Oxaliplatin iv. Biologic therapy (including but not limited to approved anti-VEGF, anti VEGFR or anti-EGFR monoclonal antibodies) v. Targeted therapy or immunotherapy if appropriate c. Adjuvant/neoadjuvant chemotherapy with or without additional anti-cancer therapy will not count as a prior regimen in the absence of recurrence during or within 6 months of completion of the last dose of planned therapy.

   Other solid tumors

   PIK3CA in tumor and/or ctDNA

   1. Other solid tumors, excluding primary CNS tumor
   2. At least 1 prior line of systemic anti-cancer therapy and no other standard therapeutic options.
   3. Tumor mutation status using a validated method such as FoundationOne®CDx must be known before enrollment. Locally available testing may also be acceptable upon discussion with the Medical Monitor.
3. Has the ability to swallow and has a functional gastrointestinal tract.
4. ECOG performance status score of 0, 1, or 2.
5. Measurable disease by RECIST 1.1. If no measurable disease by RECIST 1.1, discuss with Medical Monitor the availability of other suitable tumor markers for assessments for antitumor activity.
6. Baseline oxygen saturation on room air ≥92%.
7. LVEF >50% as per echocardiography or multi-gated acquisition scan.

8. Baseline QTc interval ≤470 msec using Fridericia's QT correction formula. Note: This criterion does not apply to participants with right or left bundle branch block or on pacemakers, but prior discussion with the Medical Monitor is required.

   Clinical Laboratory Values

9. HbA1c \<8.0%.

10. Adequate organ function, defined as follows:

    • Bone Marrow

      • Platelets ≥100,000/mm3
      • Hemoglobin ≥9.0 g/dL (can be transfused within 7 days but cannot be transfusion dependent)
      • WBC >3000/mm3
      • ANC >1500/mm3

    • Liver Function

      • Total bilirubin ≤1.5 × ULN
      • AST ≤2.5 × ULN; ALT ≤2.5 × ULN (AST, ALT ≤5 × ULN if liver metastases are present)

    • Coagulation

      • INR ≤1.5; aPTT ≤1.5 × ULN in the absence of anticoagulant therapy or within acceptable parameters per local standard of care on anticoagulant therapy.

    • Renal Function

      • Creatinine clearance ≥60 mL/min either measured or calculated using standard Cockcroft-Gault formula.
      • Albumin ≥3.0 g/dL

    Prior Therapy

11. Recovered to ≤Grade 1 toxicity from previous therapies, excluding alopecia, peripheral neuropathy, lymphopenia or therapy-related hypothyroidism or other endocrine disorders that are well controlled.
12. Demonstrated progressive disease or intolerance to the last regimen. Sex and Contraceptive/Barrier Requirements

13. Contraceptive use by participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

    1. Male Participants:

       Participants are eligible to participate if they agree to the following during the study intervention period and for at least 180 days after the last dose of study intervention:

       • Refrain from donating sperm

       PLUS, either:

       • Be abstinent from intercourse where pregnancy can occur (abstinent on a long term and persistent basis) and agree to remain abstinent

       OR

       • Must agree to use [contraception /barrier] as detailed below: Agree to use an external condom and with child-bearing potential (CBP) partner use an additional highly effective contraceptive method with a failure rate of \<1% per year as described in Section 10.4 when having sexual intercourse with a partner able to give birth who is not currently pregnant.

    2. Female Participants:

       • A participant is eligible to participate if not pregnant or breastfeeding, and one of the following conditions applies:

         • Is not of CBP.

    OR

    • Is of CBP and using a contraceptive method that is highly effective (with a failure rate of \<1% per year), with low user dependency, as described in Section 10.4, during the study intervention period and for at least 90 days after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The Investigator should evaluate the potential for contraceptive method failure (eg, noncompliance, recently initiated) in relationship to the first dose of study intervention.

      • A CBP participant must have a negative highly sensitive pregnancy test (urine or serum, as required by local regulations) during screening and before the first dose of study intervention Day 1 of Cycle 1; see Section 8.3.5.
      • Additional requirements for pregnancy testing during and after study intervention are located in Section 8.3.5.
      • The Investigator is responsible for review of medical history, menstrual history, and recent sexual activity where pregnancy can occur to decrease the risk for inclusion of a participant with an early undetected pregnancy.

    Informed Consent

14. Signed informed consent as described in Section 10.1.2, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

    Other Inclusion Criteria

15. Has a new or recent tumor biopsy (collected at screening, if feasible) or archived specimen within 5 years prior to screening.

Exclusion Criteria:

Medical Conditions

1. History (within 2 years before screening) of a malignancy that is histologically distinct from the cancers being studied with the exception of adequately treated basal cell or squamous cell skin cancers and/or ductal carcinoma in situ of the breast or other malignancies that have a very low potential for recurrence or for confounding study results.
2. Symptomatic brain metastases requiring steroids or other interventions. Participants with previously diagnosed brain metastases are eligible if treatment has been completed and the participant has recovered from the acute effects of radiation therapy or surgery prior to study entry, have discontinued corticosteroid treatment for these metastases for at least 2 weeks before the first dose of MTX-531, and are neurologically stable.
3. Known leptomeningeal metastases.
4. Concurrent congestive heart failure, prior history of class III/ IV cardiac disease (New York Heart Association), myocardial infarction within the last 6 months, unstable arrhythmias, unstable angina or other poorly controlled cardiac conditions (eg, arrhythmias) that are considered significant by the Investigator.
5. Poorly controlled diabetes mellitus (including prior HbA1c measurements or compliance).
6. Active uncontrolled systemic bacterial, viral, fungal, or parasitic infection requiring IV antibiotics.
7. Experienced prior Grade 3-4 toxicities or severe toxicities from PI3K or EGFR inhibitors.

8. Any other medical condition (eg, pulmonary, psychiatric, neurological, significant dermatologic conditions that may confound the interpretation of on-treatment toxicities or life-threatening toxicities from prior PI3K- or EGFR-directed therapies, if applicable) that in the opinion of the Investigator would place the participant at unacceptably high risk for toxicity.

   Prior/Concomitant Therapy

9. Received systemic or local anticancer therapy within 3 weeks before the first dose of MTX-531 or 5 half-lives of the drug (whichever is less).
10. Received radiotherapy within 2 weeks before the first dose of MTX-531 and has not recovered from all radiation-related toxicities. A 1-week washout is allowed for palliative radiation (≤2 weeks of treatment course) to non-CNS tumors. Inability to swallow oral medications or impaired gastrointestinal absorption due to anomalies of the gastrointestinal tract, such as gastrectomy or active inflammatory bowel disease.(Administration of oral medications via feeding tubes is not allowed.)
11. Any condition requiring chronic administration of >10 mg daily prednisone or equivalent or other immunomodulators.

12. Unable or unwilling to discontinue prohibited concomitant medications or adhere to restrictions for use of concomitant medications as defined in the protocol (see Section 6.9.2).

    Other Exclusion Criteria

13. Pregnant or nursing women