Optimizing early phase clinical trial washout periods: a report from the Therapeutic Advances in Childhood Leukemia and Lymphoma consortium

Abstract

Background

The National Cancer Institute (NCI) issued a 2021 memorandum adopting the American Society of Clinical Oncology (ASCO) and Friends of Cancer Research (Friends) task force recommendations to broaden clinical study eligibility criteria. They recommended that washout periods be eliminated for most prior cancer therapy and when required to utilize evidence- and/or rationale-based criteria. The Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) consortium responded to this guidance.

Methods

A TACL task force reviewed the consortium’s research portfolio, the relevant literature and guidance documents from ASCO-Friends, NCI, and US Food and Drug Administration to make expert consensus and evidence-based recommendations for modernizing, broadening, and codifying TACL-study washout periods while ensuring consistency with pediatric ethics, and federal regulations. TACL’s screening log was reviewed to estimate the impact that updated washout periods would have on patient inclusivity and recruitment.

Results

Over a 19-year period, 42 (14.6% of all screened ineligible patients [n = 287]) patients were identified as excluded from TACL early phase studies exclusively because of not meeting washout criteria. An additional 6 (2.1%) did not meet washout and at least 1 other exclusion criterion. A new TACL washout guidance document was developed and then adopted for use. Where washout criteria were not eliminated, rationale- and/or evidenced-based criteria were established with citation.

Conclusion

In an effort to reduce unnecessary exclusion from clinical trials, TACL created rationale- and/or evidenced-based washout period standards largely following guidance from the NCI and ASCO-Friends recommendations. These new, expanded eligibility criteria are expected to increase access to TACL clinical trials while maintaining safety and scientific excellence.

Clinical trial participation is critical to the advancement of cancer care and often provides individuals with access to therapies not otherwise available (1). Therefore, reducing unnecessary barriers to clinical trial enrollment should be a priority. The protection of human subjects, equity in access to clinical trials, and the ability to efficiently and accurately answer trial questions are cornerstones of medical research ethics (2). As such, rigorous eligibility criteria, particularly in early phase trials, are necessary. However, these criteria are sometimes inconsistent, unclear, incomplete, not evidenced-based (3,4), and not pragmatic (5-7) potentially leaving an estimated 20% of patients unnecessarily ineligible for cancer trials (8).

Based on the 2011 American Society of Clinical Oncology (ASCO) Blueprint for Transforming Clinical and Translational Cancer Research (9), ASCO and Friends of Cancer Research (Friends) assembled a task force to make recommendations on modernizing oncology clinical trial eligibility criteria. They observed that one of the most consequential barriers to trial participation was completing a protocol-required washout period from recent therapies or interventions (10). Washout periods are commonly employed to optimize patient safety by reducing overlapping drug exposures and to prevent temporal misinterpretation of on-study observations such as toxicities and therapeutic response (10). However, ASCO-Friends found no relevant literature on the science of commonly employed washout periods and noted that washout period rationale from individual studies or the sponsoring consortium was “rarely provided” (10). Ultimately, they recommended that, in most cases, time-based washout periods be removed from protocol eligibility criteria and replaced by the use of clinical and laboratory values to address exclusion criteria for safety purposes. They stipulated that circumstances do exist for which time-based washout periods may be optimal; however, in these cases, guidelines should be evidenced-based with rationale provided (10). In late 2021, the National Cancer Institute (NCI) Cancer Therapeutics Evaluation Program (CTEP) issued a memorandum announcing its endorsement of the ASCO-Friends recommendations, which are now included in CTEP protocol templates (11). In 2017 and 2020, the US Food and Drug Administration (FDA) published similar support and guidance (3,12). Some uptake of this guidance by individual investigators and consortia has occurred but remains unacceptably slow (13).

In 2022, the Pharmacy and Pharmacology Committee of the Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) consortium (https://tacl.chla.usc.edu/tacl/) formed a task force to develop and implement ASCO-Friends–inspired washout period modernization in TACL clinical trial protocol templates. Children are considered a vulnerable population (14), and therefore, additional protections are required for participation in clinical research (14,15). In addition, relapsed hematologic malignancies are often rapidly progressive, which limits the feasibility of clinical trial accrual when lengthy washout periods are required (16). Protections against undue toxicity and clinical deterioration from rapid disease progression could be addressed by thoughtful time-based washout guidance.

Here, we present the process and result of the TACL consortium’s effort to incorporate and harmonize washout periods as encouraged by ASCO-Friends, the NCI, and the FDA. This project was undertaken to 1) improve access to TACL’s novel early phase clinical trials; 2) develop consistent, complete, clear, rationale- and/or evidenced-based criteria; 3) provide a documented record of evidence used and decision-making criteria for TACL washout periods; 4) support the safety, regulatory, and ethical protections to our minor subjects; 5) continue to provide rigorous and generalizable data to advance the field of pediatric hematologic malignancies; and 6) maximize diversity and justice in our trial populations.

Process

TACL is an early phase clinical trial consortium focused solely on childhood hematologic malignancies (17). It is currently comprised of 34 member institutions in the United States and Australia. The TACL Pharmacy and Pharmacology Committee is comprised of physicians, pharmacists, and a pharmacologist all with pediatric oncology expertise. In 2021, the committee began the process of making recommendations to broaden, evidence base, and codify washout periods for TACL clinical trials. To form its recommendations, the committee reviewed all ASCO-Friends, CTEP, and FDA position papers and statements on modernizing and broadening clinical trial eligibility criteria. In addition, it performed a thorough literature search investigating adult and pediatric oncology study washout periods and their rationale (with a particular emphasis on early phase studies involving children with hematologic malignancies) as well as literature pertaining to the pharmacokinetics, pharmacodynamics, and toxicology of categories of possible past therapies to which prospective participants might have been exposed. Furthermore, when necessary, the committee sought outside expert opinions to form its recommendations. Recommendations were reviewed, revised, and approved by TACL’s governing Steering and Prioritization Committee and were published to TACL members in 2023.

To estimate the potential impact of the washout recommendations, the TACL patient screening database was interrogated. To collect high-level data to help understand the relapsed patient landscape and inform consortium priories, TACL requires that, on a monthly basis, member institutions self-report de-identified data for all relapsed hematologic malignancy patients at their site, including basic patient demographics (age, sex, race, ethnicity), disease information (type of leukemia or lymphoma with cytogenetic and molecular characterization), and whether a patient was enrolled onto a TACL trial or reason for not enrolling. As the database was not specifically developed to answer research questions, the information entered is not centrally audited. The screening database protocol was submitted to each member’s institutional review board and was either approved or determined to be exempt from review.

Data analysis

As was the case during the efforts of the ASCO-Friends Washout Period Working Group (10), we were unable to obtain suitable literature pertaining to the rationale supporting the therapeutic categories used (or omitted) or the time periods mandated within each category for industry-sponsored, investigator-initiated, or consortium-led oncology clinical trials. Although we were without the guiding principles used to create them, to better appreciate the current state of washout periods used by large academic consortia when conducting early phase pediatric hematologic malignancy clinical research, we compiled Table 1 with current, recent example, and representative criteria as a foundation on which to build our optimization project.

Table 1.

Examples of washout periods from recent pediatric early phase studies involving hematologic malignancies^a

Sponsor	TACL	TACL	COG	COG/PedAL	SJCRH	DFCI	POETIC
Study ID	T2012-002	T2016-003	AINV18P1	PEPN2113	SELCLAX	DFCI18-328	POE-14-01
ClinicalTrials.gov ID	NCT02879643	NCT03263936	NCT03792256	NCT05146739	NCT04899994	NCT03740334	NCT02512926
Investigational agent	Vincristine sulfate liposomal injection	Decitabine	Pablociclib	Uproleselan	Selinexor and venetoclax	Ribociclib	Carfilzomib
Backbone chemotherapy	UK ALLR3	Vorinostat and FLAG	VPLD	Fludarabine and Cytarabine	FLAG	Everolimus and dexamethasone	Cyclophosphamide and etoposide
Phase (target disease)	1 (R/R ALL/LL)	1 (R/R AML)	1 (R/R ALL/LL)	1 (R/R AML)	1 (R/R AML)	1 (R/R ALL)	1 (R/R ALL or AML)
Accrual era	2016-2022	2017-2020	2019-2021	2023-present	2021-present	2019-2024	2016-2023
Allowable postrelapse cytoreduction	HU	HU	HU; prednisone (≤5 days)	HU	NC	HU; VCR, 6MP, or oral MTX	NC
ALL-style maintenance chemotherapy	0 days	NC	0 days	NC	NC	0 days (no corticosteroids)	≥7 days
Myelosuppressive chemotherapy	≥10 days	≥14 days	≥14 daysb	≥14 days	≥14 days	≥14 days	≥14 days
Nonmyelosuppressive chemotherapy	≥10 days	NC	≥7 days	≥7 days	24 hours	NC	NC
Biologic agents	≥7 days	≥7 days	NC	NC	NC	NC	≥14 days
Small molecule inhibitors	NC	NC	NC	NC	NC	≥7 days	NC
Antibodies	Longer of ≥3 t1/2 of agent or 30 days	≥3 t1/2 of agent	≥21 days	≥21 days	NC	≥3 t1/2 of agent	≥14 days
Immune effector cell therapy	≥30 days	≥42 days	≥30 days	≥30 days	NC	≥42 days	NC
Hematopoietic growth factors	≥14 days for long acting; ≥7 days for short acting	≥14 days for long acting; ≥7 days for short acting	≥14 days for long acting; ≥7 days for short acting	≥14 days for long acting; ≥7 days for short acting	NC	NC	≥14 days for long acting; ≥7 days for short acting
Interleukins, interferons, or cytokines	NC	NC	≥21 days	≥21 days	NC	NC	NC
Allogeneic stem cell transplant, including DLI	≥100 days and no GVHD	No immunosuppressive therapy or GVHD	≥84 days and no GVHD	≥84 days and no GVHD	≥60 days and no GVHD	≥90 days and no GVHD	≥90 days and no GVHD
Autologous stem cell transplant	NC	NC	≥42 days	≥30 days	NC	≥60 days	NC
Local or small port XRT	≥21 days	NC	≥14 days	≥14 days	NC	0 days	≥14 days
Large port XRT	≥21 days	≥90 days	≥42 days	≥42 days	NC	NC	≥90 days
TBI, CSI, >50% of pelvis XRT	≥21 days	≥90 days	≥150 days	≥150 days	NC	≥90 days	≥90 days
XRT to non–central nervous system chloromas	NC	0 days	NC	NC	NC	NC	NC

^aData retrieved from ClinicalTrials.gov. 6MP = mercaptopurine; ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; COG = Children’s Oncology Group (childrensoncologygroup.org); CSI = craniospinal irradiation; DFCI = Dana-Farber Cancer Institute (dana-farber.org/research/departments-centers/pediatric-oncology); DLI = donor lymphocyte infusion; FLAG = fludarabine, cytarabine, and granulocyte stimulating factor; GVHD = graft vs host disease; HU = hydroxyurea; LL = lymphoblastic lymphoma; MTX = methotrexate; NC = no category (ie, category not used in washout criteria); PedAL = Leukemia and Lymphoma Society Pediatric Acute Leukemia Master Clinical Trial (lls.org/dare-to-dream/pedal); POETIC = Pediatric Oncology Experimental Therapeutics Investigators’ Consortium (poeticphase1.org); R/R = relapsed or refractory; SJCRH = St Jude Children’s Research Hospital (stjude.org); t_1/2 = half-life; TACL = Therapeutic Advances in Childhood Leukemia and Lymphoma (tacl.chla.usc.edu); TBI = total body irradiation; UK ALLR3 = VCR, mitoxantrone, dexamethasone, and asparaginase; VCR = vincristine VPLD = vincristine, prednisone, asparaginase, and doxorubicin; XRT = radiation therapy.

^bMust refer to a COG-generated list of commercial and phase 1 agents for drug classification and assigned washout period.

Interrogation of the TACL screening database for relapsed and refractory patients noted that between October 6, 2004, and September 14, 2023, a total of 1754 entries were made. There were 1306 relapse occurrences and 359 refractory occurrences at a time and at an institution that had open a potentially appropriate TACL trial for that patient. Of these occurrences, 109 (6.5%) resulted in enrollment onto TACL studies. Of the remaining 1556 patient occurrences, 287 (18.4%) were reported to not have enrolled because of not meeting study eligibility criteria and 42 (42 of 287, 14.6%) of which did not enroll exclusively because of not meeting washout period criteria with an additional 6 (6 of 287, 2.1%) not meeting washout period criteria and at least 1 additional reason. Of the 42 relapsed or refractory occurrences that did not result in enrollment exclusively for not meeting washout period criteria, if the updated washout periods criteria had been in place at the time of their screening, 7 patient occurrences would definitely still have not resulted in eligibility (all relapsed shortly after hematopoietic stem cell transplant and/or had high-grade graft vs host disease); 9 patient occurrences would definitely have resulted in eligibility, and for 26 patients, the database did not contain enough data to definitively determine eligibility. Therefore, 35 (35 of 287, 12.2%) patient occurrences would have or could have resulted in eligibility for TACL studies had the updated washout criteria been in place at the time of their screening. In univariate analyses, no statistically significant differences were found in age, sex, race, ethnicity, and presence of Down syndrome between this group of 35 patient occurrences and the group of 109 patient occurrences that resulted in enrollment onto TACL studies (data not shown).

Recommendations

The following represent the consensus and evidenced-based recommendations.

Recommendation 1: recovery from prior therapy

Patients must have recovered from the acute nonhematologic toxic effects of all prior therapy, defined as a return to Common Terminology Criteria for Adverse Events grade of no more than 2 for all acute toxicities. Chronic toxicities from prior anticancer therapy must be stable (defined as not worsening for at least 28 days) and be a grade of no more than 2.

Rationale

This criterion addresses the primary recommendation from ASCO-Friends stating that laboratory parameters should be used in place of time-based washout periods to address safety considerations (10). Baseline hematologic toxicities were exempted as they are almost universally present in relapsed hematologic malignancies and are often related to the progression of the disease (18). Chronic conditions from prior therapies should also be tolerated as they are unlikely to spontaneously progress or interfere with patient safety.

Recommendation 2: therapies permitted without washout

Certain antineoplastic agents require no washout and are permitted during a potential participant’s screening period. This is particularly important in patients with rapid disease progression and/or disease-related clinical instability (Table 2).

Table 2.

Therapies requiring no washout or permitted during washout-screening period

Timing	Drug	Dose	Route	Frequency	Duration
At relapse	Acute lymphoblastic leukemia–style maintenance therapya	As below in footnote (a)	Any	Any	Any
	Small molecule- and tyrosine kinase- inhibitorsb	As appropriate for specific drug	Oral	Any	Chronic onlyb
	Steroid administered for physiologic replacementc,d	As below in footnote (c)	Any	Any	Any
After relapsee	Hydroxyurea	Any	Oral	Any	Any
	Intrathecal therapyf	Age based	Intrathecal	Once	One time
	Corticosteroid administered at intubationd,g	Any	Any	Once	One time
	Corticosteroid administered for stress dosingd,h	Any	Any	Any	≤3 days
	Prednis(ol)one	≤20 mg/m2 per dose	Oral or intravenous	No more than twice daily	≤5 days
	Dexamethasone	≤3 mg/m2 per dose	Oral or intravenous	No more than twice daily	≤5 days
	Mercaptopurine	≤75 mg/m2 per dose	Oral	Once daily	Any
	Methotrexate	≤20 mg/m2 per dose	Oral	Once weekly	Any
	Cytarabine	≤100 mg/m2 per dose	Intravenous or subcutaneous	Once daily	≤5 days
	Etoposide	≤75 mg/m2 per dose	Oral	Once daily	≤5 days

^aAny combination of drugs, doses, and durations that are accepted and/or published ALL maintenance regimens. These regimens generally include vincristine, a steroid (eg, dexamethasone or prednisone), mercaptopurine, low-dose methotrexate, and intrathecal therapy.

^bTo allow no washout, tyrosine kinase inhibitor must have been taken for at least 28 days at time of relapse.

^cAny steroid and dose that is given for the purposes of treating physiologic adrenal insufficiency.

^dSteroids administered for physiologic replacement, stress dosing, or intubation do not count toward the 2 antineoplastic therapies allowable for disease stabilization.

^eAntineoplastic therapies permitted after relapse are intended for patients with unstable and/or increasing peripheral blood leukemic blast counts or rapidly progressing extramedullary disease (in the documented opinion of the investigator). A maximum of 2 therapies on this list may be initiated during the washout period either concomitantly or in succession (8). The investigator is encouraged to deliver the minimum amount of therapy for the shortest period of time, which still allows disease stabilization during screening. Any therapy started after relapse for disease stabilization must be stopped at least 24 hours prior to the start of protocol therapy.

^fMethotrexate, hydrocortisone, cytarabine, or any combination thereof.

^gSteroid given for the purpose of reducing inflammation during intubation.

^hStress dose steroids may be administered per institutional standards for patients who have exogenous glucocorticoid dependence and/or are adrenally insufficient with concern for minor illness or fever (in the opinion of the investigator).

Rationale

Chemotherapeutic agents given at low doses with well-defined toxicity profiles, such as acute lymphoblastic leukemia–style maintenance and single agent small molecule inhibitors or tyrosine kinase inhibitors, should not require washout periods—an approach that is consistent with ASCO-Friends recommendations (10). In addition, acute leukemias and high-grade lymphomas are highly proliferative diseases that often prohibit therapy-free periods. To be as inclusive as possible, disease mitigation strategies to prevent acute decompensation should be allowed to bridge a potential patient during the trial screening process. These drugs should have generally mild and predictable toxicities and rapid clearance pharmacokinetics and should not aggressively treat the underlying disease (19) such as to preserve the ability to accurately grade trial therapy toxicity and disease response.

Recommendation 3: cytotoxic chemotherapy requiring washout

Cytotoxic chemotherapy is defined as any standard cancer-directed therapy not otherwise defined in this document. Of note, acute use (defined as <28 consecutive days) of small molecule inhibitors or tyrosine kinase inhibitors are considered cytotoxic chemotherapy. At least 7 days must have elapsed since the completion of cytotoxic therapy with the following exceptions that require a minimum of a 14-day washout period: any PEGylated and/or liposomal therapy (eg, pegaspargase, calaspargase, cytarabine, and daunorubicin liposomal injection (CPX-351 [Vyxeos]); high-dose methotrexate (≥1 g/m² per dose); high-dose cytarabine (≥1 g/m² per dose).

Rationale

There is a moderate risk of consequential and unpredictable toxicities associated with all chemotherapies but particularly those not listed in Table 2 (19). Therefore, all cytotoxic chemotherapeutics not included in Table 2 will require at least a 7-day washout. A limited list of medications will require a 14-day washout. These medications are those known to have protracted acute side effect profiles and include high-dose methotrexate (eg, stroke-like syndrome, mucositis) (20) or high-dose cytarabine (eg, cerebellar toxicities) (21) and those with prolonged pharmacokinetics clearance such as drugs that are liposome encapsulated (22) or PEGylated (23). Consequential toxicities from tyrosine kinase inhibitor use largely occur and are recognized within the first 28 days of use and over that time self-resolve, resolve after dose reduction, resolve after symptomatic care, or resolve after drug discontinuation (24). This is particularly true of those toxicities that would impact the safety or evaluability of early phase clinical trials in hematologic malignancies (eg, myelosuppression, hepatic toxicity, dermatitis, acute cardiac toxicity) (24). Longer-term toxicities, although consequential, are rare (generally occurring in <10% of patients) (25), and therefore, no washout period is required after chronic use is established (≥28 days).

Recommendation 4: washout required for antibody-drug conjugates

Washout of at least 21 days after the last dose of any antibody-drug conjugates is required.

Rationale

Establishing a washout time for antibody-drug conjugates is complicated as antibody-drug conjugates may be considered 2 different drugs: the monoclonal antibody and the payload (10). In addition, antibody-drug conjugates as a class have a wide range of half-lives and toxicities (26). Specific agents (ie, inotuzumab and gemtuzumab) (26,27) are known to be associated with delayed hepatotoxicity and/or sinusoidal obstruction syndrome (26,27), which can be life-threatening. Therefore, it seems prudent to require at least a 21-day washout period for this class of agents to ensure patient safety and accurate response interpretation.

Recommendation 5: washout required after monoclonal antibodies including bispecific antibodies

For FDA-approved (any indication) monoclonal antibodies (including bispecific T-cell engagers and dual affinity retargeting therapies), at least 3 half-lives of the antibody or 21 days (whichever is shorter) must have elapsed. Half-life is defined as the long end of the FDA label pharmacokinetics description (pediatric data preferred but adult data are acceptable). If steroids are being used to modify drug-derived immune-related adverse effects of antibody therapy, at least 7 days must have elapsed since the last dose of corticosteroid.

Rationale

The most frequent adverse effects associated with monoclonal antibodies (including bispecific T-cell engagers and dual affinity retargeting therapies) are limited to the peri-administration period and/or rapidly reversible upon therapeutic discontinuation (28). Furthermore, meaningful toxicities are almost always contained to on-target effects (28) and/or are rapidly reversible (29,30). Finally, concerns of clouding investigational therapeutic efficacy are minimal when the most recent therapy has failed the patient (10). As such, washout should be limited to 3 half-lives for those with rapid pharmacokinetics clearance and a maximum of 21 days for those with longer clearance kinetics. Agent-specific half-life is available in FDA labeling materials (ie, package inserts). For antibodies with no adult or pediatric FDA label, the washout period would be the maximum 21 days.

Recommendation 6: washout required after hematopoietic growth factors, interleukins, interferons, and cytokines

At the time of enrollment, it must have been at least 7 days since the completion of therapy with growth factors (eg, filgrastim or biosimilar, sargramostim); at least 14 days since the completion of therapy with pegfilgrastim (or biosimilar); at least 21 days after the completion of interleukins, interferon, or cytokines (other than hematopoietic growth factors).

Rationale

Administration of cell cycle–specific cytotoxic chemotherapy in close temporal relationship to myeloid growth factors can result in profound myelosuppression, and therefore, adequate separation between such therapies is required. Interleukins, interferons, and cytokines can cause consequential changes in the tumor microenvironment and clinically can cause significant acute and subacute toxicities (31); as such, reasonable separation from these therapies from a novel agent is recommended. Finally, these periods are broadly accepted standards across multiple research consortia (32,33).

Recommendation 7: washout required after immune effector cell therapies

At least 30 days after the completion of any type of immune effect cell therapy (eg, tumor vaccines, chimeric antigen receptor T cells) must have elapsed. If, after 30 days, steroids are being used to modify immune-related adverse events, at least 7 days must have elapsed since the last dose of corticosteroid.

Rationale

The onset of acute toxicities that are unique to immune effector cell therapies, including cytokine release syndrome, immune effector cell–associated neurotoxicity syndrome, and immune effector cell–associated hemophagocytic lymphohistiocytosis-like syndrome, are reported to occur within days to a few weeks following infusion, usually prior to day 30 (34-37).

Recommendation 8: washout required after stem cell infusions

Consensus washout times for commonly used stem cell infusions were based on evidence (19,32,33,38-44) and expert opinion and is listed in Table 3.

Table 3.

Washout periods for recent prior stem cell infusions (with or without total body irradiation)

Stem cell infusion	Washout period	Evidence to support washout period
Allogeneic hematopoietic stem cell transplant	≥84 days  • In addition to 90-day washout, potential participants must have no evidence of ongoing acute or chronic GVHD and are not receiving GVHD prophylaxis or treatmenta	• The 84-day washout after hematopoietic stem cell transplant is a standard period among multiple consortia (32,33), and this posttransplant period is one during which multiple significant toxicities occur (27). • It is standard to exclude participants if they have evidence of GVHD and/or are on therapy to suppress GVHD (32,33).   • The addition of a novel therapeutic may exacerbate GVHD (41,44) compromising patient safety and possibly confounding study results.
Unmodified autologous stem cell transplant or infusion, including boost infusion	≥30 days and achieved bone marrow recoveryb	• Most acute toxicities after autologous are secondary to the conditioning regimen used for preparation (39,40), and most chemotherapy-related toxicities occur within 4 weeks of administration (19,41,44). • Most other nonconditioning-related toxicities occur secondary to lack of engraftment (41,44).
Donor lymphocyte infusion	≥30 days	• Greater than or equal to grade 2 acute GVHD has been documented to occur after donor lymphocyte infusion in 11%-34% of patients and usually within 4 weeks (42,43).

^aGVHD limited to the skin only for which the patient is either not receiving therapy or topical therapy only and no more than grade 2 may be eligible at the discretion of the study chair. It is reasonable to consider patients who have skin-only GVHD but not on topical-only therapy as most novel agents will not impact skin physiology (unless the novel agent is thought to have targeted dermatologic toxicities). GVHD = graft vs host disease.

^b Bone marrow recovery is defined as an absolute neutrophil count of at least 500 cells/µL x 2 peripheral blood assessments done at least 24 hours apart.

Recommendation 9: washout after radiation and radiopharmaceutical therapy

Consensus washout times for radiation and radiopharmaceutical therapy was based on evidence (19,45-48) and expert opinion and is listed in Table 4.

Table 4.

Washout periods for recent prior radiation therapy

Radiation therapy	Washout period	Evidence to support washout period
Total body irradiation	≥84 days	• 84 days after the end of total body irradiation is relatively standard across relapsed leukemia studies in other major consortia (32,33). • In addition, at least 84 days is standard for the washout after hematopoietic stem cell transplant, which often includes total body irradiation.
Craniospinal irradiation	≥42 days	• 42 days after the end of craniospinal irradiation is based on literature suggesting that recovery from craniospinal irradiation–induced bone marrow suppression is expected within 4-6 weeks (45) and demonstrated tolerable hematologic and infectious toxicities 6 weeks following craniospinal irradiation in studies of children receiving myelosuppressive adjuvant chemotherapy (47).   • Given that these studies involved patients with de novo central nervous system tumors and not relapsed blood malignancies, the longer time period was chosen out of caution.
Systemic radiopharmaceutical therapy	≥42 days	• Radiopharmaceuticals tend to have long half-lives and prolonged effects (46); with common significant adverse events (myelosuppression, hepatotoxicity, nephrotoxicity) involving organs critical to the safety and evaluability of early phase clinical trials in hematologic malignancies (48). • 42 days after radiopharmaceutical therapy is also standard across other consortia (32,33).
Whole brain radiotherapy	≥14 days	• 14 days after whole brain radiotherapy or stereotactic radiation therapy is standard across multiple other consortia (32,33) and is what is recommended by American Society of Clinical Oncology–Friends of Cancer Research (10).
Stereotactic radiation therapy	≥14 days
Extramedullary site radiation with a field is ≤10 × 10 cm	No washout (0 days)	• The amount of bone marrow suppression and other organ toxicity from either extracranial radiation in the area of 10 x 10 cm or in local ocular radiation would be minimal, and therefore, no washout period should be imposed (K. Wong, MD, email, and oral personal communication, May 2022)a.
Local ocular radiotherapya	No washout (0 days)

^aThe presumed acute adverse events from local ocular radiotherapy should be limited largely to dry eye syndrome (56,57); myelosuppression should not occur because bone marrow exposure with local ocular radiotherapy is estimated to be 8%-10% of that received during whole brain radiation therapy (56,57); however, investigators would also need to be cognizant of potential toxicities such as retinitis, decreased vision, retinal detachment, and/or conjunctivitis. If the investigational agent has specific known effects in these areas, separating radiation adverse effects from those of radiation may be challenging, and individual protocols should weigh this when developing the washout period for radiation.

Recommendation 10: concomitant complementary and alternative medications (CAMs)

Patients who are receiving any CAM, including cannabidiol or medical marijuana, are ineligible but will be eligible immediately upon discontinuing such medications and/or supplements for the duration of the trial. Routine dietary multivitamins or supplemented naturally occurring hormones (eg, melatonin) are permitted at the discretion of the investigator.

Rationale

There has been a rapid increase in the use of CAM over the last several decades (49). Furthermore, cannabidiol and marijuana have become legal in an increasing number of states and municipalities (50). However, there are meaningful interactions between CAM and prescribed drugs. Many of these interactions are well documented (49) including poor outcomes in patients concomitantly receiving cannabis or cannabidiol and checkpoint inhibitors (50,51). Ultimately, there are known and unknown effects of these products on prescribed medications, and therefore, the concomitant use of CAM should not be permitted during studies, but no washout after discontinuation appears necessary.

Recommendation 11: therapeutic modalities not otherwise named in this document

Potential participants who have received an intervention intended to treat their primary malignancy that does not fall into one of the above categories will require a minimum 30-day washout from that intervention, and the patient must be discussed with the study chair or designee who may determine a longer washout period as necessary.

Rationale

The therapeutic landscape of cancer care is rapidly evolving with novel classes of antineoplastics being introduced into clinical care almost continuously (52-54). Although this document is intended to remain comprehensive and current, it is anticipated that situations may arise where a potential participant has been exposed to a recent therapy not addressed in this document. The pharmacology and toxicology of such novel interventions cannot be anticipated. Therefore, it is prudent to match the longest nonradiotherapy and/or non–stem cell transplant washout period suggested otherwise in this document (ie, 30 days is the washout for immune effector cell therapies and donor lymphocyte infusion). In addition, active discussion with the study chair or designee should be enforced in the best interest of patient safety and study stewardship.

Discussion

Establishing the minimal, pragmatic (5-7), and yet evidenced- and/or rationale-based restrictions for a possible clinical trial population is best for beneficence, distributive justice, and effectively and efficiently moving the field forward (55). With the ASCO-Friends collaboration trailblazing the conversation on modernizing oncology inclusion criteria, the TACL consortium followed. A review of the TACL screening database revealed that at least 14% of relapsed patient occurrences did not enroll on a TACL trial solely because of restrictive washout criteria with more than 12% either definitely or possibly being eligible if the updated washout criteria had been in effect at the time of their screening. Reevaluating such criteria was a potentially impactful place to begin the TACL protocol eligibility modernization process. Secondary to unique challenges in the design of protocols including children and those with relapsed hematologic malignancies, we determined we could not eliminate time-based washout periods. We were able to use evidence and consensus expert opinion to recommend washout guidelines that were substantially less restrictive while maintaining commitments to patient safety and study integrity. To our knowledge, TACL is the first major consortium to publish a response to the NCI call to modernize eligibility criteria—with detailed documentation of evidence used—and we hope making such a document publicly available will inspire discourse and innovation in the area of clinical trial inclusivity. TACL has committed to make its washout guidance a “living document” that will be regularly reevaluated and updated as new information becomes available. We have also initiated our next project to modernize—and broaden—eligibility criteria around historical anthracycline exposure and cardiac function restrictions.

Data availability

De-identified participant data that support the findings of this article will be shared upon approved written request at 2 years after this article publication for 7 years from the publication date. These data will be available to researchers who provide a methodologically sound proposal for the purposes of achieving specific aims outlined in that proposal. Proposals should be directed to TACL Consortium Central Inbox TACL@chla.usc.edu (Attention: TACL Consortium Administrative Director, Erika Shin-Kashiyama, JD) and will be reviewed by TACL Steering and Prioritization Committee. Requests to access data to undertake hypothesis-driven research will not be unreasonably withheld. To gain access, data requesters will need to sign a data access agreement and to confirm that data will only be used for the agreed purpose for which access was granted.

Author contributions

Eric S. Schafer, MD, MHS (Conceptualization; Formal analysis; Investigation; Methodology; Writing—original draft), Deepa Bhojwani, MD (Supervision; Validation; Writing—review & editing),Yeuh Yun Chi, PhD (Data curation; Validation; Writing—review & editing), Andrew E. Place, MD, PhD (Validation; Writing—review & editing), Susan R. Rheingold, MD (Validation; Writing—review & editing), Nirali N. Shah, MD, MHSc (Validation; Writing—review & editing),Todd M. Cooper, DO (Validation; Writing—review & editing), Bill H. Chang, MD, PhD (Validation; Writing—review & editing), Alan S. Wayne, MD (Supervision; Validation; Writing—review & editing), Kenneth Wong, MD (Investigation; Writing—review & editing), Laura B. Ramsey, PhD (Investigation; Writing—review & editing), Lauren Pommert, MD, MS (Investigation; Writing—review & editing), Nicole Kaiser, PharmD, BCOP (Conceptualization; Investigation; Writing—review & editing), Susan I. Colace, MD (Investigation; Writing—review & editing), Colleen Annesley, MD (Investigation; Writing—review & editing), Kristine R. Crews, PharmD, BCPS (Investigation; Writing—review & editing), Teresa Rushing, PharmD, BCPS, BCOP (Investigation; Methodology; Writing—review & editing), Himalee S. Sabnis, MD, MSc (Investigation; Writing—review & editing), and M. Brooke Bernhardt, PharmD, MS, FCCP (Conceptualization; Investigation; Methodology; Writing—review & editing).

Funding

This project was supported in part by the Higgins Family Charitable Foundation. NNS is supported by the Intramural Research Program, Center of Cancer Research, National Cancer Institute and NIH Clinical Center, National Institutes of Health (ZIA BC 011823). ASW was supported in part by National Cancer Institute award P30CA014089.

Conflicts of interest

ESS has attended advisory board meetings for Beam Therapeutics and Jazz Pharmaceuticals. LBR has consulted for and received research funding from BTG Specialty Pharmaceuticals. NNS receives research funding from Lentigen, VOR Bio, and CARGO Therapeutics and has attended advisory board meetings for VOR, ImmunoACT, and Sobi (no honoraria). TMC has consulted for Day One Biopharmaceuticals. SRR serves on an Abbvie steering committee and a Pfizer data safety monitoring committee. AEP receives research funding from AbbVie, Servier and Jazz; has attended advisory board meetings for Novartis and Servier; and has served as a scientific advisor for AbbVie and Triterpenoid Therapeutics. ASW receives research funding from Kite, a Gilead Company (to his institution). TR, KRC, CA, SIC, NK, LP, HSS, KW, BHC, TMC, YYC, DB, and MBB have nothing to declare.