Tegavivint for the Treatment of Recurrent or Refractory Solid Tumors, Including Lymphomas and Desmoid Tumors

B
Brian Weiss

Primary Investigator

Enrolling By Invitation
12-30 years
All
Phase 1/2
147 participants needed
2 Locations

Brief description of study

What is the purpose of this study?
This phase I/II trial evaluates the highest safe dose, side effects, and possible benefits ofgavivint in treating patients with solid tumors that has come back (recurrent) or does notd to treatment (refractory). Tegavivint interferes with the binding of beta-catenin to TBL1, which may help stop the growth of tumor cells by blocking the signals passed from oneule to another inside a cell that tell a cell to grow.

THIS STUDY IS ENROLLING BY INVITATION ONLY - Consistent with most oncology trials, patients are not actively “recruited,” but are screened by their physician for appropriate clinical trial(s) at the time of their routine clinic visit. Occasionally, a patient may be a self-referral or physician referral, but are still screened for appropriate clinical trials at the time of their routine clinic visit. PI and staff may send copies of relevant consent forms to these patients to look over prior to actually consenting or enrolling them. This may take place at the patient's visit at which the consent is presented or the patient's next visit to the outpatient hematology/oncology clinic.

Interested in participating? For more information about this research study or other cancer-related clinical trials at IU Simon Comprehensive Cancer Center, please contact:
IU Clinical Trials Office 
Phone: (317) 278-5632

Detailed description of study

PRIMARY OBJECTIVES:
I. To estimate the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) ofgavivint administered as an intravenous (IV) infusion over 4 hours, once weekly for 3 weeks, followed by a 1 week rest, in a 28-day cycle to pediatric patients withurrent/refractory solid tumors, including non-Hodgkin lymphoma and desmoid tumors. (Phase 1 Dose Escalation) II. To preliminarily define antitumor activity of tegavivint in pediatricwith recurrent or refractory Ewing sarcoma, liver tumors (hepatocellular carcinoma [HCC] and hepatoblastoma), osteosarcoma, Wilms tumor, desmoid tumors, and tumors with Wnthway aberrations. (Phase 2) III. To define and describe the toxicities of tegavivintdministered on this schedule. (Phase I) IV. To characterize the pharmacokinetics ofgavivint in pediatric patients with recurrent or refractory cancer. (Phase I)
SECONDARY OBJECTIVE:
I. To preliminarily define the antitumor activity of tegavivint for pediatric patients withurrent/refractory solid tumors, including lymphoma and desmoid tumors within the confinesPhase 1 study.
EXPLORATORY OBJECTIVES:
I. To test whether baseline activity of the WNT/beta catenin pathway correlates with clinicalusing archived tumor tissue.
II. To characterize pharmacodynamic changes in tumor tissue to examine target engagement bygavivint.

What will happen during the study?
  • This is a phase I, dose-escalation study followed by a phase II study.
  • Patients receive tegavivint IV over 4 hours on days 1, 8, and 15 of each cycle. Treatmentvery 28 days for up to 26 cycles or 24 months in the absence of disease progressionunacceptable toxicity. Patients undergo an x-ray at baseline, after cycle 1, and thenvery 3 cycles while on treatment and a dual x-ray absorptiometry (DEXA) scan at baseline,very 6 cycles while on treatment, at months 12 and 24, and then annually up to 60 monthswing end of therapy.
  • After completion of study intervention, patients are followed up every 3 months for 12hs, every 6 months for 24 months, and then annually for 60 months.

Eligibility of study

You may be eligible for this study if you meet the following criteria:

  • Conditions: Riley, Colorectal Carcinoma, Endometrial Carcinoma, Melanoma, Neuroblastoma, Ovarian Carcinoma, Pancreatic Ductal Adenocarcinoma, Recurrent Desmoid Fibromatosis, Recurrent Ewing Sarcoma, Recurrent Hepatoblastoma, Recurrent Hepatocellular Carcinoma, Recurrent Malignant Solid Neoplasm, Recurrent Non-Hodgkin Lymphoma, Recurrent Osteosarcoma, Refractory Desmoid Fibromatosis, Refractory Ewing Sarcoma, Refractory Hepatoblastoma, Refractory Hepatocellular Carcinoma, Refractory Malignant Solid Neoplasm, Refractory Non-Hodgkin Lymphoma, Refractory Osteosarcoma, Solid Pseudopapillary Neoplasm of the Pancreas, Wilms Tumor
  • Age: Between 12 Months - 30 Years
  • Gender: All

Inclusion Criteria:
  • PART A: Patients must be >= 12 months and =< 21 years of age at the time of study
  • PART B: Patients must be >= 12 months and =< 30 years of age at the time of study
  • Patients with recurrent or refractory solid tumors including non-Hodgkin lymphoma anddesmoid tumors are eligible. Patients must have had histologic verification ofgnancy at original diagnosis or relapse
  • PART A: Patients with relapsed or refractory solid tumors, including patients withHodgkin lymphoma and desmoid tumors
  • PART B: Patients with recurrent or refractory Ewing sarcoma, desmoid tumors,ver tumors (HCC and hepatoblastoma), Wilms tumor, and tumors with Wnthway aberrations. For the Wnt pathway aberrations cohort we will include the mostCTNNB1 mutations (S37F, S45F, T41A, S45P, S33C, S37C, D32Y, S33F, T41I, G34R,G34V, D32N, S33P, G34E, D32G) as well as any loss of function mutations in the APC,Axin2FBXW7, TCF7L2, and RNF43 genes or any gain-of-function mutations in the GSK3B,LRP6, and LGR5 genes. For patients without prior sequencing, immunohistochemistry(IHC), is required. IHC showing strong nuclear beta-catenin staining will be acceptedhe following tumor types: colorectal carcinoma, melanoma, endometrial cancer,varian cancer, neuroblastoma, non-Hodgkin lymphoma, pancreatic ductal adenocarcinoma,d solid pseudopapillary tumor of the pancreas
  • PART A: Patients must have either measurable or evaluable disease. For desmoid tumors,he patient must have disease that the investigator deems unresectable or sufficientlybid or potentially life-threatening that there is favorable risk/benefit to thehe trial
  • PART B: Patients must have measurable disease. For desmoid tumors, the patient musthave measurable disease that the investigator deems unresectable or sufficientlybid or potentially life-threatening that there is favorable risk/benefit to thehe trial
  • Patients must have a performance status corresponding to Eastern Cooperative OncologyGroup (ECOG) scores of 0, 1 or 2. Use Karnofsky for patients > 16 years of age andLansky for patients =< 16 years of age
  • Patients must have fully recovered from the acute toxic effects of all priorherapy and must meet the following minimum duration from priordirected therapy prior to enrollment. If after the required timeframe, theumerical eligibility criteria are met, e.g., blood count criteria, the patient isdered to have recovered adequately.
    • Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive
      • Solid tumor patients: >= 21 days after the last dose of myelosuppressivehemotherapy (42 days if prior nitrosourea)
      • Non-Hodgkin lymphoma patients
        • A waiting period prior to enrollment is not required for patientsving standard maintenance chemotherapy (i.e., corticosteroid,vincristine, thioguanine [6MP], and/or methotrexate)
        • >= 14 days must have elapsed after the completion of other cytotoxicherapy, with the exception of hydroxyurea, for patients not receivingdard maintenance therapy
        • NOTE: Cytoreduction with hydroxyurea must be discontinued >= 24 hourshe start of protocol therapy
    • Anti-cancer agents not known to be myelosuppressive (e.g., not associated with
      reduced platelet or absolute neutrophil counts [ANC]): >= 7 days after the lastdose of agent
    • Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody,d toxicity related to prior antibody therapy must be recovered to grade =< 1
    • Corticosteroids: If used to modify immune adverse events related to priorherapy, >= 14 days must have elapsed since last dose of corticosteroid
    • Hematopoietic growth factors: >= 14 days after the last dose of a long-actinggrowth factor (e.g., pegfilgrastim) or 7 days for short acting growth factor. Forgents that have known adverse events occurring beyond 7 days afterdministration, this period must be extended beyond the time during which adversevents are known to occur
    • Interleukins, interferons and cytokines (other than hematopoietic growth): >= 21 days after the completion of interleukins, interferon orytokines (other than hematopoietic growth factors)
    • Stem cell Infusions (with or without total-body irradiation [TBI]):
      • Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stemusion including donor lymphocyte infusion (DLI) or boost infusion:>= 84 days after infusion and no evidence of graft versus host disease (GVHD)
      • Autologous stem cell infusion including boost infusion: >= 42 days.
    • Cellular therapy: >= 42 days after the completion of any type of cellular therapy
      (e.g., modified T cells, natural killer [NK] cells, dendritic cells, etc.).
    • External beam radiation therapy (XRT)/external beam irradiation including: >= 14 days after local XRT; >= 150 days after TBI, craniospinal XRT ordiation to >= 50% of the pelvis; >= 42 days if other substantial bone marrow(BM) radiation
    • Radiopharmaceutical therapy (e.g., radiolabeled antibody, iobenguane I-131 [131IBG]): >= 42 days after systemically administered radiopharmaceutical therapy
    • Patients must not have received prior exposure to tegavivint
  • PATIENTS WITH SOLID TUMORS WITHOUT KNOWN BONE MARROW INVOLVEMENT: Peripheral absolute
    neutrophil count (ANC) >= 1000/uL (within 7 days prior to enrollment)
  • PATIENTS WITH SOLID TUMORS WITHOUT KNOWN BONE MARROW INVOLVEMENT: Platelet count >=100,000/uL (transfusion independent, defined as not receiving platelet transfusions7 days prior to enrollment) (within 7 days prior to enrollment)
  • PATIENTS WITH SOLID TUMORS WITHOUT KNOWN BONE MARROW INVOLVEMENT: Hemoglobin >= 8.0g/dL at baseline (may receive red blood cell [RBC] transfusions) (within 7 days prior)
  • Patients with known bone marrow metastatic disease will be eligible for study providedhey meet blood counts (may receive transfusions provided they are not known to bey to red cell or platelet transfusions). These patients will not be evaluablehematologic toxicity. At least 5 of every cohort of 6 patients must be evaluablehematologic toxicity for the dose-escalation part of the study. If dose-limitinghematologic toxicity is observed, all subsequent patients enrolled on Part A must bevaluable for hematologic toxicity
  • Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70L/min/1.73 m^2 or a creatinine based on age/gender as follows (within 7 days prior to):
    • Age; maximum serum creatinine
    • Age 1 to < 2 years; 0.6 mg/dL (male); 0.6 mg/dL (female)
    • Age 2 to < 6 years; 0.8 mg/dL (male); 0.8 mg/dL (female)
    • Age 6 to < 10 years; 1 mg/dL (male); 1 mg/dL (female)
    • Age 10 to < 13 years; 1.2 mg/dL (male); 1.2 mg/dL (female)
    • Age 13 to < 16 years; 1.5 mg/dL (male); 1.4 mg/dL (female)
    • Age >= 16 years; 1.7 mg/dL (male); 1.4 mg/dL (female)
  • PATIENTS WITH SOLID TUMORS: Bilirubin (sum of conjugated + unconjugated or total) =<
    1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment)
  • PATIENTS WITH SOLID TUMORS: Serum glutamic pyruvic transaminase (SGPT) (alanine[ALT]) =< 135 U/L. For the purpose of this study, the ULN for SGPT is5 U/L (within 7 days prior to enrollment)
  • PATIENTS WITH SOLID TUMORS: Albumin >= 2 g/dL (within 7 days prior to enrollment)
Exclusion Criteria:
  • Pregnant or breast-feeding women will not be entered on this study because there isyet no available information regarding human fetal or teratogenic toxicities.Pregnancy tests must be obtained in girls who are post-menarchal. Males or females ofductive potential may not participate unless they have agreed to use twove methods of birth control, including a medically accepted barrier orve method (e.g., male or female condom) for the duration of the study.Abstinence is an acceptable method of birth control
  • Patients receiving corticosteroids who have not been on a stable or decreasing dose ofd for at least 7 days prior to enrollment are not eligible. If used todify immune adverse events related to prior therapy, >= 14 days must have elapseddose of corticosteroid
  • Patients who are currently receiving another investigational drug are not eligible
  • Patients who are currently receiving other anti-cancer agents are not eligible
  • Patients who are receiving cyclosporine, tacrolimus or other agents to preventgraft-versus-host disease post bone marrow transplant are not eligible for this trial
  • Patients who are currently receiving drugs that are strong inducers or inhibitors ofCYP3A4 are not eligible. Strong inducers or inhibitors of CYP3A4 should be avoided14 days prior to the 1st dose of tegavivint to the end of the study
  • Patients who have received bisphosphonates within 4 weeks prior to study enrollmentwill be excluded
  • Patients who have received denosumab within 180 days prior to study enrollment will beuded
  • Patients with primary brain tumors are ineligible
  • Patients with known central nervous system (CNS) metastasis, except forharyngeal tumors, will be excluded
  • Patients with a known metabolic bone disease (ex: hyperparathyroidism, Paget'sdisease, osteomalacia) are not eligible
  • Patients with a disorder associated with abnormal bone metabolism will be excluded
  • Patients with grade >= 2 hypocalcemia that is not corrected with oral calciumupplementation will be excluded
  • Patients with vitamin D < 20 ng/mL will require supplementation, or will otherwise beuded. Patients must agree to take vitamin D +/- calcium supplements (if necessary)ding to institutional or published guidelines. Additional calcium supplementationquired if adequate dietary intake can be ascertained
  • Patients with pre-existing grade 3 osteoporosis are excluded
  • Patients who have an uncontrolled infection are not eligible
  • Patients who have received a prior solid organ transplantation are not eligible
  • Patients who in the opinion of the investigator may not be able to comply with they monitoring requirements of the study are not eligible

Updated on 14 Sep 2024. Study ID: PEPN2011, PHO-COG-PEPN2011, 13690
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