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Overly Restrictive Clinical Trial Exclusion Criteria May Block Patients From Receiving Effective Therapy

December 30, 2021

Many clinical trials exclude patients with comorbidities, active or recent malignancies, organ dysfunction, or poor performance status, meaning that clinical trials typically enroll the "Olympic athletes of patients," according to clinical trial researchers who spoke with ASH Clinical News about clinical trials' eligibility criteria in a recent feature article ("Who's In and Who's Out?"). Such stringent criteria might limit "unfit" patients' access to potentially beneficial investigational therapies, according to a study published in Leukemia.

"Only 3 to 5 percent of patients with cancer treated in the United States enroll in clinical trials," authors, led by Guillermo Montalban Bravo, MD, from the Department of Leukemia at the University of Texas MD Anderson Cancer Center, wrote, with strict clinical trial eligibility criteria likely playing a role in these low participation rates. [The authors wanted] to determine whether patients who were excluded from new therapeutic intervention studies [could be enrolled] within a monitored clinical trial safely, and whether they would derive benefit.

To test this concept, Dr. Montalban Bravo and investigators designed a clinical trial for patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) who would be considered unfit for traditional clinical trials. Patients were treated with the hypomethylating agent azacitidine or the histone deacetylase inhibitor vorinostat – both of which have demonstrated an acceptable toxicity profile in previous clinical trials.

Patients were included if they were >17 years old with at least one of the following:

  • serum creatinine ≥2 mg/dL
  • total bilirubin ≥2 mg/dL
  • an Eastern Cooperative Oncology Group Performance Status of 3-4
  • ineligibility to participate in a protocol of higher priority due to comorbidities, other active malignancies, or malignancies with a remission period of <2 years

Patients were excluded if they:

  • had favorable cytogenetic abnormalities, such as inv(16), t(16;16), t(8;21), or t(15;17)
  • received prior anti-leukemic therapies (except hydroxyurea for cytoreduction in case of proliferative disease)

The researchers also closely monitored patients for potential toxicity and response, implementing the following stopping rules in the study protocol:

  • Survival: The study would stop if 60-day survival was unlikely (<5%) to be ≥20% compared with the historical group.
  • Response: The study would stop if complete response (CR) was unlikely (<10%) compared with the historical group.
  • Toxicity: The study would stop if the rate of grade ≥3 adverse events (AEs) were >20% at any time.

The initial exploratory study included 30 patients with previously untreated AML (n=14; 47%) and MDS (n=16; 53%) who were consecutively enrolled at the University of Texas MD Anderson Cancer Center between September 2009 and December 2010.

Patients were randomized 1:1 to receive a five-day schedule of 75 mg/m2 of azacitidine daily, with or without three daily doses of 200 mg of vorinostat. Treatment continued for up to 12 cycles unless disease progression or intercurrent illness occurred or if patients requested discontinuation. After 12 cycles, patients could continue to receive azacitidine alone.

The median follow-up was 7.4 months (range = 0.3-29 months), with patients receiving a median of 3.5 treatment cycles (range = 1-12 cycles).

Sixty-day survival (the study's primary endpoint) was 83 percent (n=24); the stopping rule for survival was never met.

Patients with AML and MDS experienced similar levels of overall survival (OS; 5.9 vs. 7.9 months; hazard ratio [HR] = 0.67; 95% CI 0.32-1.4; p=0.308) and event-free survival (EFS; 3.5 vs. 4.4 months; HR=0.74; 95% CI 0.34-1.57; p=0.432). The overall response rate (ORR) was 40 percent (n=12), with 27 percent of patients (n=8) achieving CR. Two patients went on to receive allogeneic hematopoietic cell transplantation (alloHCT).

Most patients (70%; n=21) experienced at least one AE, the most common of which were gastrointestinal toxicity and febrile neutropenia. Eight patients (27%) had treatment held or withdrawn due to AEs. At four and eight weeks, early mortality was 10 percent and 20 percent, respectively.

The authors noted that the presence of more than one eligibility criteria (what are typically considered exclusion criteria in clinical trials) was associated with a lower likelihood of 60-day survival (p=0.04). "[These results] show that treating this patient population within a clinical trial is feasible," the authors wrote, adding that "a majority of patients were able to complete at least one cycle of therapy without major toxicity and obtain clinical benefit with acceptable responses and survival despite their high comorbidity burden."

The authors expanded the study to include 79 patients who were enrolled between September 2011 and March 2014 and who were randomized to receive azacitidine (n=27; 34%) or azacitidine plus vorinostat (n=52; 66%).

The median follow-up was 22.7 months (range = 12.6-47.5 months), with patients receiving a median of three treatment cycles (range = 1-12 cycles). Seventy-nine percent of patients were alive at 60 days (n=62) and, unlike in the exploratory study, patients with MDS in this expanded study experienced longer median OS with a trend toward significance (10.6 vs. 4.4 months; HR=0.5; 95% CI 0.1-8.3; p=0.07) and significantly longer EFS (5.7 vs. 2.9 months; HR=0.1; 95% CI 0.3-0.8; p=0.04), compared with patients with AML. The ORR was slightly higher in the expanded patient cohort (47%; n=37), with 25 percent of patients achieving CR (n=20). Patients responded after receiving a median of two treatment cycles (range = 1-12 cycles), and the mediation duration of response was 7.4 months (range = 4.9-9.9 months).

Most patients (82%; n=65) experienced at least one AE, with grade 3 fatigue, dyspnea, and neutropenic fever being the most common. However, the stopping rule for toxicity was not met.

More than one-third of patients (39%; n=31) died during study treatment due to infections (42%; n=13), cardiovascular events (6%; n=2), or unknown causes (52%; n=16). Forty-eight patients went on to receive subsequent therapy, including alloHCT (n=8; 10%). At the time of the study's publication, 85 percent of patients (n=67) had died, with four- and eight-week early mortality at 10 percent and 19 percent, respectively.

"These findings suggest relaxation of [organ dysfunction, poor performance status, and other comorbidities] exclusion criteria may increase the pool of clinical trial candidates and allow access to potential beneficial therapies for patients with an otherwise dismal prognosis," Dr. Montalban Bravo and authors concluded. "These [exclusion] criteria are in place more to protect the drug or intervention being studied as opposed to the patients. … Such stringent criteria may limit the access of ‘unfit' patients to potentially beneficial therapies and limit our ability to extrapolate the safety and efficacy outcomes of new drugs being tested in conventional clinical trials to this subset of patients with unfavorable clinical features."

Limitations include the heterogeneous patient population, which limits the ability to extrapolate outcomes to specific patient populations. In addition, quality of life was not assessed, which is an important clinical outcome in a patient population with high comorbidities and decreased expected survival.


Montalban Bravo G, Huang X, Jabbour E, et al. A clinical trial for patients with acute myeloid leukemia or myelodysplastic syndromes not eligible for standard clinical trials. Leukemia. 2016 November 18. [Epub ahead of print]


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